Benzobicycloalkane

ABSTRACT

Benzobicycloalkane amines, their pharmacologically acceptable addition salts, intermediates therefore the processes for their preparation and use. The compounds of the invention exert analgesic and anti-inflammatory activity.

CROSS-REFERENCE TO COPENDING APPLICATION

This application is a divisional of copending application Ser. No.262,849, filed June 14, 1972, and now U.S. Pat. No. 3,836,670, which isa continuation-in-part of application Ser. No. 200,517, filed Nov. 19,1971, now abandoned, which is a continuation-in-part of application Ser.No. 94,983, filed Dec. 3, 1970, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to compositions of matter classified in the artof chemistry as amine derivatives of 5,8-methano-benzocyclohexane,5,8-methano-benzocycloheptane, 5,9-methano-benzocycloheptane,5,9-methano-benzocyclooctane, 5,10-methano-benzocyclooctane,5,10-methanobenzocyclononane, 5,11-methano-benzocyclononane,5,11-methanobenzocyclodecane, 5,12-methanobenzocyclodecane, or5,12-methanobenzocycloundecane, and the non-toxic acid addition saltsthereof, which in standard pharmacological tests in animals exhibitanalgesic and anti-inflammatory activity, and to processes for makingand using such compositions.

SUMMARY OF THE INVENTION

The invention sought to be patented in a principal composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formula I: ##STR1## wherein R is hydrogen,lower alkyl, lower alkyloxy, hydroxy, acyloxy, phen(lower)alkyloxy,halogen, or trifluoromethyl; R¹ is lower alkyl, lower alkenyl, orphen(lower)alkyl; R² is hydrogen, lower alkyl, or phen(lower)alkyl; R³is hydrogen, lower alkyl, phen(lower)alkyl, lower alkenyl, or alkynyl;and n is an integer from 2 to 6; and the pharmaceutically non-toxicaddition salts thereof.

The tangible embodiments of the composition aspect of the inventionpossess the inherent general physical properties in the acid salt formof being high melting, white crystalline solids, substantially solublein water and polar organic solvents such as lower aliphatic alcohols andthe like. Examination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic analysis, infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Theaforementioned physical characteristics taken together with themicroanalytical data, the nature of the starting materials and the modeof synthesis positively confirm the structures of the compositionssought to be patented.

The tangible embodiments of the principal composition aspect of theinvention possess the inherent applied use characteristics of exertingan analgesic effect in animals as evidenced by standard pharmacologicaltests. The analgesic activity of the compositions can be demonstrated byfollowing a modification of the test procedure described by D'Amour andSmith in Journal of Pharmacology 72:74 (1941), an accepted test foranalgesic agents. In this test rats are administered the compoundorally, intraperitoneally or intramuscularly and the time required forresponse to a pain stimulus caused by a high intensity beam of lightshining on the tail measured. The compounds of the invention exhibitanalgesic activity in rats at a dose of from 3.15 mg. to 125 mg. perkilogram of body weight orally and intraperitoneally, and from 0.16 to10.0 mg. per kilogram of body weight intramuscularly.

The invention sought to be patented in a principal process aspect isdescribed as residing in the concept of a sequence of reactionsincluding: introducing by alkylation in the presence of a strong baseinto the 1 position of a 2-tetralone, which is 1-alkyl, 1-alkenyl, or1-phen(lower)alkyl substituted, an ω-lower alkyl sulfonyl-,ω-phenylsulfonyl, or ω-tetrahydropyranyloxy-alkyl substituent; ifpresent, hydrolyzing the tetrahydropyranyloxy group and converting theresulting alcohol into a suitable leaving group; treating the ω-halo-,ω-lower alkyl sulfonyl-, or ω-phen-sulfonyl compound with strong base toeffect ring closure; then either reacting the tricyclic ketone directlywith ammonia or an amine at elevated temperature with removal of water,and reducing the intermediate imine to produce an amine embodiment ofthe principal composition aspect; or reacting with hydroxylamine underbasic conditions to form an oxime which is reduced to form a primaryamine embodiment of the principal compositions aspect.

The invention sought to be patented in a subgeneric composition aspectis described as residing in the concept of a chemical compound ofFormula I wherein n is 4, or 5.

The tangible embodiments of said subgeneric composition aspect possessthe inherent applied use characteristic of exerting analgesic effects inwarm-blooded animals as evidenced by pharmacological evaluation bystandard test procedures.

The invention sought to be patented in a second subgeneric compositionaspect is described as residing in the concept of a chemical compound ofFormula I wherein n is 2 or 3.

The tangible embodiments of said subgeneric composition aspect possessthe use characteristic of exerting analgesic effects in warm-bloodedanimals and in addition possess the use characteristic of exertinganti-inflammatory effects in animals as evidenced by standardpharmacologic tests. The anti-inflammatory activity of the compositioncan be demonstrated by following a test procedure described by Winter etal. in Proceedings of the Society of Experimental Biology and Medicine:111:554 (1962) and by Buttle et al. in Nature 179: 629, (1957), agenerally accepted test for anti-inflammatory agents. In this test thecompound is administered orally as a solution or suspension in distilledwater to a group of six rats. After one hour edema in the paw of therats is elicited by injection into the paw of a 1% solution ofcarrageenin. Paw volume is measured immediately and after 3 hours. Theability of the compounds to reduce the volume of the edema so producedwhen compared to a like number of control animals is a measure ofanti-inflammatory activity. The compounds of the invention exhibitanti-inflammatory activity in rats at a dose of from 50 mg. to 100 mg.per kilogram of body weight.

The invention sought to be patented in a second principle compositionaspect resides in the concept of a chemical compound having thestructure represented by Formula Ia: ##STR2## wherein R is as definedhereinabove; R¹ is lower alkyl, or phen(lower)alkyl; R⁴ is lower alkyl;R⁵ is lower alkyl and n is an integer from 2 to 6; and thepharmaceutically non-toxic addition salts thereof.

The tangible embodiments of said second principle composition aspect ofthe invention possess the inherent general physical properties in theacid salt form of being high melting, white crystalline solids,substantially insoluble in water and polar organic solvents and thelike. Examination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic analysis, infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Theaforementioned physical characteristics taken together with themicroanalytical data, the nature of the starting materials and the modeof synthesis positively confirm the structures of the compositionssought to be patented.

The tangible embodiments of said second principle composition aspect ofthe invention possess the inherent applied use characteristics ofexerting an analgesic effect in warm-blooded animals as evidenced bystandard pharmacological tests.

The invention sought to be patented in its third composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formula II: ##STR3## wherein R, R¹, and n areas hereinbefore described.

The tangible embodiments of the third composition aspect of theinvention possess the inherent general physical characteristics of beinginsoluble in water but soluble at elevated temperatures in polar organicsolvents such as lower aliphatic alcohols and the like.

Examination of the compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic analysis infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions sought to be patented.

The tangible embodiments of the third composition aspect of theinvention possess the inherent applied use characteristic of beingintermediates in the production of the amines of Formula I.

The invention sought to be patented in a fourth composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formula III: ##STR4## wherein R, R¹ and n areas hereinbefore described.

The tangible embodiments of the fourth composition of matter aspect ofthe invention possess the inherent general physical characteristic ofbeing high boiling liquids which are substantially insoluble in waterbut soluble in common organic solvents such as di(lower)alkyl ethers,di(lower)alkyl ketones, lower aliphatic alcohols, chloroform, and thelike. Examination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic analysis, infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions to be patented.

The tangible embodiments of the fourth composition aspect of theinvention possess the inherent applied use characteristics of beingintermediates for the preparation of the amines of Formula I.

The invention sought to be patented in a fifth composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formula IV: ##STR5## wherein R, R¹ and n are ashereinbefore described, with the proviso that R is not hydroxyl and Yrepresents a bromine, chlorine, lower alkyl sulfonyl, phensulfonyl ortetrahydropyranyloxy radical.

The tangible embodiments of the fifth composition of matter aspect ofthe invention possess the inherent general physical characteristics ofbeing high boiling liquids which are substantially insoluble in waterbut soluble in common organic solvents such as di(lower)alkyl ethers,di(lower)alkyl ketones, lower aliphatic alcohols, chloroform and thelike. Examination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectrographic analysis infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions to be patented.

The tangible embodiments of the fifth composition aspect of theinvention possess the inherent applied use characteristic of beingintermediates in the production of the amines of Formula I.

The invention sought to be patented in a sixth composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formula V: ##STR6## wherein R, R¹, R² and n areas hereinbefore described.

The tangible embodiments of the sixth composition of matter aspect ofthe invention possess the inherent general physical characteristics inthe acid salt form of being high melting, white crystalline solids,substantially soluble in water and polar organic solvents such as loweraliphatic alcohols and the like. Examination of compounds producedaccording to the hereinafter described process reveals, upon infraredand nuclear magnetic resonance spectroscopic analysis, infrared andnuclear magnetic resonance spectral data confirming the molecularstructure hereinbefore set forth. The aforementioned physicalcharacteristics taken together with the nature of the starting materialsand the mode of synthesis positively confirm the structures of thecompositions sought to be patented.

The tangible embodiments of the sixth composition aspect of theinvention possess the inherent applied use characteristics of beingintermediates in the production of the amines of Formula I.

The invention sought to be patented in a seventh composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formula XVI: ##STR7## wherein X is: ##STR8## R⁶is lower alkyl, or phen(lower)alkyl, and when X is ##STR9## loweralkenyl or hydroxy methyl; and R, R², R³, R⁴, R⁵ and n are as definedhereinabove, and the pharmaceutically non-toxic addition salts thereof.

The tangible embodiments of said seventh composition of matter aspect ofthe invention possess the inherent general physical properties in theacid salt form of being high melting white crystalline solids,substantially soluble in water and polar organic solvents such as loweraliphatic alcohols and the like. Examination of compounds producedaccording to the hereinafter described process reveals upon infrared andnuclear magnetic resonance spectroscopic analysis, infrared and nuclearmagnetic resonance spectral data confirming the molecular structurehereinbefore set forth. The aforementioned physical characteristicstaken together with the microanalytical data, the nature of the startingmaterials and the mode of synthesis positively confirm the structures ofthe compositions sought to be patented.

The tangible embodiments of the seventh composition aspect of theinvention possess the inherent applied use characteristics of exertingan analgesic effect in warm-blooded animals as evidenced by standardpharmacological tests.

The invention sought to be patented in an eighth composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formula XVII: ##STR10## wherein R⁷ is hydroxy,alkoxy, or when R⁸ is not alkoxy carbonyl, R², R⁸ is R⁶ or alkoxycarbonyl; and R, R², R⁶, and n are as defined hereinabove.

The tangible embodiments of said eighth composition of the inventionpossess the inherent general physical characteristics of being insolublein water but soluble at elevated temperatures in polar organic solventssuch as lower aliphatic alcohols and the like.

Examination of the compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic analysis infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions sought to be patented.

The tangible embodiments of the eighth composition aspect of theinvention possess the inherent applied use characteristic of beingintermediates in the production of the amines of Formula XVI.

The invention sought to be patented in a ninth composition aspect of theinvention resides in the concept of a chemical compound having thestructure represented by Formula XVIII: ##STR11## wherein R, R⁸ and nare as hereinbefore described.

The tangible embodiments of the ninth composition of matter aspect ofthe invention possess the inherent general physical characteristics ofbeing high boiling liquids which are substantially insoluble in waterbut soluble in common organic solvents such as di(lower)alkyl ethers,di(lower)alkyl ketones, lower aliphatic alcohols, chloroform, and thelike. Examination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectroscopic anaylsis, infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions to be patented.

The tangible embodiments of the ninth composition aspect of theinvention possess the inherent applied use characteristics of beingintermediates for the preparation of the amines of Formula XVI.

The invention sought to be patented in a tenth composition of matteraspect resides in the concept of a chemical compound having thestructure represented by Formula XIX: ##STR12## wherein R, R⁸, Y and nare as hereinbefore described, with the proviso that R is not hydroxyl.

The tangible embodiments of the tenth composition of matter aspect ofthe invention possess the inherent general physical characteristics ofbeing high boiling liquids which are substantially insoluble in waterbut soluble in common organic solvents such as di(lower)alkyl ethers,di(lower)alkyl ketones, lower aliphatic alcohols, chloroform and thelike. Examination of compounds produced according to the hereinafterdescribed process reveals upon infrared and nuclear magnetic resonancespectrographic analysis infrared and nuclear magnetic resonance spectraldata confirming the molecular structure hereinbefore set forth. Thephysical characteristics taken together with the nature of the startingmaterials and the mode of synthesis positively confirm the structure ofthe compositions to be patented.

The tangible embodiments of the tenth composition aspect of theinvention possess the inherent applied use characteristic of beingintermediates in the production of the amines of Formula XVI.

The invention sought to be patented in a second process aspect isdescribed as residing in the concept of a process for inducing analgesiain warm-blooded animals by administering to warm-blooded animals, apharmaceutically effective dose of a compound of Formula I, Formula Ia,or Formula XVI.

As used herein the term "lower alkyl" means a saturated hydrocarbonradical, including the straight and branched radicals having from 1 to 4carbon atoms, among which are for the purposes of illustration, butwithout limiting the generality of the foregoing, methyl, ethyl,n-propyl, n-butyl, and i-butyl. The term "lower alkenyl" means anunsaturated hydrocarbon radical, including straight and branchedradicals, having from 3 to 5 carbon atoms, among which are for thepurposes of illustration but without limiting the generality of theforegoing, allyl, 2-butenyl, 3-methyl-2-butenyl, 2-methyl-2-butenyl, and2-pentyl. The term lower alkynyl means an unsaturated hydrocarbonradical, containing a triple bond, including straight and branchedradicals, having from 3 to 6 carbon atoms, among which are for thepurposes of illustration, but without limiting the generality of theforegoing 3-propynyl, 2-butynyl, 1-butyn-3-yl, and3-methyl-1-butyn-4-yl. The term "phen(lower)alkyl" means a lower alkylradical as defined hereinabove substituted in a terminal position by aphenyl or a phenyl radical substituted by lower alkyl or lower alkyloxy,among which are for the purposes of illustration but without limitingthe generality of the foregoing benzyl, phenethyl, o, m, or p-anisyl, por m-cumenyl, veratryl, o, m, or p-xylyl. The term "phensulfonyl" meansa phenyl or substituted phenyl sulfonic acid radical among which are,for the purposes of illustration, but without limiting the generality ofthe foregoing, phenyl sulfonyl, or p-toluene sulfonyl. The term"acyloxy" means either an aliphatic or aromatic carboxylic acid radical;if aliphatic, it may contain from 2 to 7 carbon atoms either straightchain, branched or concatenated to form a carbocyclic ring, among whichare for the purposes of illustration but without limiting the generalityof the foregoing acetic, propionic, butyric, i-butyric,cyclohexanecarboxylic, cyclopentanecarboxylic; if aromatic, it maycontain an unsubstituted aromatic nucleus or the aromatic nucleus ringsubstituted by lower alkyl, among which are for the purposes ofillustration but without limiting the generality of the foregoing,benzoic, o, m, or p-toluic, p or m-ethylbenzoic.

DESCRIPTION OF THE PREFERRED EMBOIDMENTS

In describing the processes for the preparation of the specificembodiments of the invention, reference will be made to FIG. A whereinthe compounds are assigned Roman numerals for identificationschematically, and wherein is illustrated schematically the reactionsequence for preparing specific primary amine embodiments of Formula I,namely6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine(XI),12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methano-5H-benzocyclononen-3-ol(XIV), and12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methano-5H-benzocyclononen-3-ol,acetate (XV); specific secondary amine embodiments of Formula I, namelyN-allyl-6,7,8,9,10,11,-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine(X) andN,5-dimethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-amine(Xa); specific tertiary amine embodiments of Formula I, namelyN-allyl-N,5-dimethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine(XIII); a specific embodiment of Formula II, namely6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,oxime (IX); a specific embodiment of Formula III, namely6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one(VIII); and a specific embodiment of Formula IV, namely1-(4-chlorobutyl)-1-methyl-7-methoxy-2-tetralone (VII).

Referring now to FIG. A, the starting materials for the invention,1-alkyl, 1-alkenyl, or 1-phen(lower)alkyl-2-tetralones, may be preparedfrom commercially available 2-tetralones, by a well-known alkylationreaction as typically described by Stork and Schulenberg in the Journalof the American Chemical Society, 84, 284 (1962). The tetralones aretreated with pyrrolidine in an inert solvent such as benzene, and thenreacted with the appropriate lower alkyl, lower alkenyl, orphen(lower)alkyl halide in an inert solvent, such as benzene or dioxane,at elevated temperatures, conveniently the reflux temperature of thesolvent employed. They may also be prepared from a suitable commerciallyavailable 1-tetralone which may be treated as described by Howell andTaylor in the Journal of the Chemical Society, 1958, 1249 with aGrignard reagent, prepared from the appropriate lower alkyl, loweralkenyl, or phen(lower)alkyl halide, and the resulting 1-substituteddihydro-naphthalene oxidized with peracid.

Syntheses of non-commercially available tetralones are readily availablein the literature, e.g. the synthesis of α-tetralone is described inOrganic Synthesis, Collective Volume IV, page 898; the synthesis ofβ-tetralone is described in the same work on page 903; and a generalsynthesis of β-tetralones is described in Nagata et al. Netherlands Pat.No. 67,09534, Jan. 10, 1968.

The first step in preparing the aforementioned embodiments is theportionwise addition, in the cold, of a strong base, such as asuspension of sodium hydride in benzene, to a stirred solution of1-methyl-7-methoxy-2-tetralone (VI) and 1-bromo-4-chloro-butane, indimethyl formamide, followed by a period of stirring at roomtemperature, to produce compound VII. Compound VII is converted to thebridged tetralone VIII by treatment with a strong base, preferablysodium hydride, in an inert solvent, preferably dimethyl formamide. Thebridged tetralone VIII so produced is then used as an intermediateeither for the production of the oxime IX or if desired for theproduction of the secondary amine Xa.

In order to prepare the oxime IX the bridged tetralone VIII is treatedwith hydroxylamine under basic conditions. The oxime IX may be isolatedby conventional means and is used as an intermediate for the productionof the primary amine XI. To prepare the amine XI the oxime IX is treatedeither with hydrogen in the presence of a catalyst, preferably Raneynickel, an ammonium hydroxide, at moderate pressure, preferably 40-50psi; the hydride reducing agents, for example lithium aluminum hydride;diborane at elevated temperature; or an alkali metal, preferably sodiumin an alkanol, for example ethanol or isopropanol. When using catalyticreduction the reaction proceeds stepwise and the corresponding imine ofFormula V may be isolated as an intermediate, and then may be reduced tothe desired primary amine. The amine XI is isolated by conventionalmeans. To prepare the amine Xa, the bridged tetralone VIII is treatedwith an excess of methyl amine. The substitution is carried out withremoval of water, conveniently in the presence of calcium oxide, at anelevated temperature, preferably 180°-190° C. When the amine has aboiling point below the desired temperature the reaction isconveneiently carried out in a sealed pressure vessel. The intermediateimine so produced may be reduced as obtained directly from thesubstitution reaction. The amine Xa is produced by treating this iminewith either ##STR13## hydrogen in the presence of a catalyst, preferablyplatinum oxide, at moderate pressure, preferably 40-50 psi; the hydridereducing agents, for example lithium aluminum hydride or sodiumborohydride; diborane at elevated temperature, or an alkali metal,preferably sodium, in an alkanol, for example ethanol or isopropanol.The primary amine XI may also be converted to the secondary amine X bysubstitution reactions well-known in the art of organic chemistry. Aconvenient method is to treat with one mole equivalent of allyl bromide.The substitution is carried out in the presence of an organic acidacceptor, preferably di-isopropyl ethyl amine, in an organic solvent ata temperature of from about 60° C. to 140° C. Benzene and xylene areparticularly useful solvents but it will be apparent to an organicchemist that any solvent can be used which will not interfere with thecourse of the reaction. For convenience the reflux temperature of thesolvent selected can be employed. The secondary amine X is isolated byconventional methods.

If desired the secondary amine X can be methylated to give the N-methyltertiary amine XII. A preferred method for the methylation reaction isto first carbethoxylate the secondary amine by treatment with ethylchloroformate in an unreactive organic solvent, such as methylenechloride or chloroform. For best results, a weak inorganic base, such assodium bicarbonate or potassium carbonate, is added to the reactionmixture. The temperature of the carbethoxylation reaction is notcritical and, for convenience, room temperature is used. It will beobvious to one skilled in organic chemistry that for the purposes ofthis reaction other halo formate esters would be equivalent to ethylchloroformate. The carbethoxylated amine is then reacted with a reducingagent, preferably lithium aluminum hydride, in an inert solvent,preferably ether or tetrahydrofuran, to afford the N-methyl tertiaryamine XII which is isolated by standard procedures.

A preferred method of preparation of the tertiary amine XIII is to firstacylate the secondary amine X with acetyl chloride in a basic organicsolvent, preferably pyridine, at an elevated temperature, convenientlythe reflux temperature of the solvent selected. The acylated amine isthen reacted with a reducing agent, preferably lithium aluminum hydride,in an inert solvent preferably ether or tetrahydrofuran, to afford thetertiary amine XIII which is isolated by standard techniques.

The primary amine XI which bears a lower alkyloxy substituent can behydrolyzed to the phenolic compound XIV. A particularly useful method isto treat the primary amine with 48% aqueous hydrobromic acid at elevatedtemperature, conveniently reflux temperature. The crystalline product isisolated by standard techniques. It will be obvious to one skilled inthe art of organic chemistry that the hydrolysis reaction may beperformed on the bridged tetralone VIII and that the phenolic compoundso formed would then be the full equivalent of all other compounds notbearing such a substituent in all subsequent reactions.

The phenolic amine XIV may be acetylated to produce the acetylderivative XV. A skilled organic chemist will recognize that in order toacetylate the phenolic function a primary or secondary amine must firstbe reacted with a suitable protecting group. Carbobenzoxy chloride isparticularly convenient for this purpose. The protected derivative isthen treated with acetic anhydride and the protecting group removed,conveniently, in the case of the carbobenzoxy group by hydrogenolysis.It will be obvious to a skilled organic chemist that any desiredacylation reagent may be substituted for the acetic anhydride. Theacylation reaction may also be accomplished by exposure of the phenolicamine, suitably distributed on an inert carrier, conveniently potassiumbromide powder, to a suitably volatile acylating agent, in the vaporstate, at temperatures moderately higher than room temperature,conveniently 40°-70° C.

While the processes of the invention have been specifically describedwith reference to the drawing which illustrates their applicationto1-methyl-7-methoxy-2-tetralone it will be readily apparent to oneskilled in the art of organic chemistry that the processes will beequally applicable to tetralones bearing, in the 1 and 7 positions,other substituents contemplated within the scope of the invention.Similarly it will be obvious to vary the chain length of thepolymethylene compound in order to produce the variously sized ringsystems encompassed by the invention. A skilled chemist will readilyrecognize that, in addition to the α,ω-dihalopolymethylene, anypolymethylene compound of the desired chain length, which bears, assubstituents in the terminal positions, suitable leaving groups, such as(lower)alkylsulfonyl or phensulfonyl, or one such leaving group and agroup, such as tetrahydropyranyloxy which may be readily converted to aleaving group, may be utilized in the initial cycloalkylation process.The substitution of other strong bases, such as alkali metal alkoxides,in suitable solvents, for the illustrated sodium hydride will also beapparent to one skilled in the art. It will be obvious to one skilled inthe art that, if the α,ω-disubstituted polymethylene does not bear atetrahydropyranyl substituent, the complete cycloalkylation may beperformed without isolation of the intermediate, compound VII. Oneskilled in the art will recognize that it is possible to substituteanhydrous ammonia for methyl amine in the imination of compound VIII andthat reduction will then give compound XI. The substitution of otherlower alkyl, and phen(lower)alkyl amines, for methylamine, to givesecondary amines analogous to compound Xa will similarly be apparent toone skilled in the art. Other lower alkyl halides, lower alkenylhalides, phen(lower)alkyl halides, or lower alkynyl halides may besubstituted for allyl bromide in the treatment of compound XI to obtainthe secondary amines encompassed by the invention. Similarly other loweralkanoyl, lower alkenoyl, phen(lower)alkanoyl or lower alkynyl halidesmay be used in the preparation of the tertiary amine embodiments of theinvention.

The amine oxides of Formula Ia are prepared by oxidation, convenientlywith an organic peracid, of the di(lower)alkyl tertiary amineembodiments of Formula I.

One knowledgeable in the art of organic chemistry will recognize that1-alkyl-substituted 2-indanones and 2-benzsuberones can becycloalkylated in a fashion similar to that described for thecycloalkylation of 1-alkyl substituted 2-tetralones. The compounds soformed can then be further treated by the processes describedhereinabove to produce derivatives which are the full equivalents of thecompounds of Formula I described herein.

The substituted tetralones described hereinabove and their equivalentindanone and benzsuberone analogues may be substituted at various otherpositions on the aromatic ring with such radicals as lower alkyl, loweralkyloxy, halo and trifluoromethyl and these may be employed as startingmaterials in the initial cycloalkylation reactions and such compoundscan then be treated by the processes described hereinabove, to produceamino derivatives bearing these variously located substituents.

Preparation of the indanones of Formula XVI may also be accomplished bycyclization of appropriate known o-phenylene diacetic acid diesters toproduce 1-alkoxycarbonyl-2-indanones. Alkylation to produce the 1-alkoxycarbonyl-indanones of Formula XIX may be accomplished by standardalkylation techniques. Alternatively the keto group of the alkoxycarbonylindanone may be treated with a suitable ketone protectingreagent, such as ethylene glycol, a lower alkyl, lower alkenyl, orphen(lower)alkyl group may be introduced into the 1-position by standardalkylation techniques, the protective group removed from the ketone, theester function hydrolyzed, and the carbonyl group eliminated bydecarboxylation. The resulting lower alkyl, lower alkenyl, orphen(lower)alkyl-2-indanone may then be treated similarly to thecorresponding tetralones to produce the lower alkyl, lower alkenyl orphen(lower)-cyclic system of Formula XVIII may be accomplished asdescribed for the corresponding tetralones of Formula IX. Preparation ofthe imino derivatives of the benzobicyclic ketones derived from theabove described indanones may be accomplished in a fashion similar tothat described for the preparation of the imino derivatives of thebenzobicyclic ketones derived from tetralones. A skilled organic chemistwill of course recognize that the alkoxy carbonyl substitutedbenzobicyclic ketones may be converted to oximino derivatives but thattreatment with ammonia or primary amine will result in side reactionswith the alkoxy carbonyl group.

The skilled organic chemist will of course not use catalytic reductionmethods involving the use of ammonia or primary amines.

The alkoxy carbonyl benzobicyclic ketone may, if desired, be treatedwith a suitable ketone protecting reagent, such as ethylene glycol, thealkoxy carbonyl group may then be reduced to a hydroxy methyl group, andthe keto group regenerated. This compound may then be converted into thehydroxy methyl imino compounds of Formula XVII by the above describedmethods.

Reduction of the oximes or imines of Formula XVII to the amines ofFormula XVI may be accomplished by the same reduction methods as used toprepare the amines of Formula I. Those embodiments of Formula XVIIcontaining an alkoxycarbonyl will, of course, simultaneously beconverted to the embodiments of Formula XVI which have ahydroxy(lower)alkyl substituent. If desired the hydroxyl group may beremoved by standard means, such as tosylation and reduction with lithiumaluminum hydride. Ordinarily this process will result in an N-tosylamine from which the free amine may be recovered by hydrolysis. Thevariously other substituted amines of Formula XVI may be prepared fromappropriate primary or secondary amines or embodiments of Formula XVI byprocesses similar to those described for the preparation of thevariously substituted amines of Formula I.

It will be obvious to one skilled in the art of chemistry that thebenzobicyclic ketones of Formula III and Formula XVIII will be producedas racemic mixtures, and that reduction of either oximes of Formula IIand Formula XVII or imines of Formula V and Formula XVII will yield theamines of Formula I and Formula XVI as diasteromers. The separation ofthe diastereomeric pairs and their resolution into enantiomers, ifdesired, may be accomplished by well-known procedures. The diastereomersenantiomers and mixtures thereof are all included within the scope ofthis invention.

It is convenient in the present application to distinguish pairs ofdiastereomers by specifying the orientation of the amino group. A numberof conventional systems of nomenclature for specifying the orientationare suitable, and selection of a particular system is a matter ofconvenience. Because of its greater specificity and more generalapplicability, a system enabling specification of the relativeorientation of all substituents on the tetralin ring system has beenadopted for use in this application. In this system the tetralin ring isprojected on a plane. Those substituents extending below the plane aredesignated α, and those extending above the plane are designated β.

In the process for the use of the amines of Formula I and Formula XVI orpharmaceutical acceptable salts thereof, they may, if desired, beformulated with pharmaceutically acceptable carriers in accordance withmethods well-known in the art.

It will be obvious to those skilled in the art that N-oxides of thedialkyl substituted tertiary amines of Formula XVI may be prepared in afashion similar to that described for the preparation of the N-oxides ofFormula Ia. These N-oxides are the full equivalents of those embodimentsof the invention specifically described.

An alternate synthesis of the amines of Formula I and Formula XVI isthrough the preparation of a compound of the formula: ##STR14## whereinR, R¹, and n are as defined hereinabove; and m is 0 or 1, as describedby Wiesner, Chau and Demerson in Tetrahedron Letters, 1965, page 2893,followed by either dehydration and hydrogenation of the resulting doublebond, or tosylation and cleavage of the tosyl group. This route is thepreferred method of synthesis for those embodiments wherein n is 2 or 6.

The tangible embodiments of the principal composition aspect have beenfound to possess the additional applied use characteristic of exertingmorphine antagonism effects in animals when tested in standardpharmacological evaluation procedures. The morphine antagonism effectscan be demonstrated by administering the compound to morphine addictedmonkeys. A morphone antagonist precipitates morphine withdrawalsymptons. The morphine antagonism effect can also be demonstrated bydosing groups of three male Charles River rats subcutaneously withmorphine at 75 mg/Kg of base. The degree of narcosis induced by themorphine is measured at 15 and 30 minutes after injection. Criteria areloss of righting reflex, tail and body rigidity and respiratorydepression. Test compounds are administered intramuscularly, 40 minutesafter the morphine. The degree of antagonism is measured at 20 minuteintervals for 2 hours. Nalorphine, at 2 mg/kg, serves as a positivecontrol while one group of morphinized rats in each determinationreceives no antagonist and serves as negative controls. Reversal of theloss of righting reflex constitutes a positive response.

The following examples illustrate the best mode contemplated by theinventors for preparing the compositions of the invention.

EXAMPLE I 1-(4-Chlorobutyl)-1-Methyl-7-Methoxy-2-Tetralone

1-Methyl-7-methoxy-2-tetralone (57 g.), tetramethylene chlorobromide(200 g.) and dimethyl formamide (250 ml.) are introduced into a twoliter reaction vessel which is fitted with a condenser and drying tube,a mechanical stirrer, a nitrogen inlet, a thermometer, and a soft rubberstopper. After this solution is cooled to 10° C. a suspension of sodiumhydride (approximately 8 g. freed of mineral oil by washing withbenzene) in benzene (100 ml.) is added slowly in 10 ml. portions,through the rubber stopper with the aid of a syringe. The temperature ismaintained between 12° and 20° for the 1.5 hour addition period. Thereaction is then allowed to warm to room temperature, stirred for 3 1/2hours, and poured into ice water (1.5 1.). The layers are separated, theaqueous phase extracted with ether, the combined organic phases washedwith saturated saline, dried over sodium sulfate and the organicsolvents removed under reduced pressure. Distillation of the residueyields the title product (62.5 g.) b. p. 155-185° C. (approximately 0.3mm).

I. r. analysis: 5,85, 7.95 μ

EXAMPLE II 1-(3-Bromopropyl)-1-Methyl-2-Tetralone

Sodium hydride (0.75 g.) washed free of mineral oil is added in smallportions, over a period of 45 minutes, to a well stirred solution of1-Methyl-2-tetralone (4.8 g.) and 1,3-dibromopropane (24 g.) in benzene(100 ml.) while maintaining the temperature at 25° C. The mixture isstirred at room temperature for 1 hour and heated at reflux for 2 hours.When cool 2 drops of acetic acid are added and the mixture clarified byfiltration through diatomaceous earth. Concentration of the filtrate anddistillation of the resulting residue gives the title product (4.5 g.)b.p. 130°-135° C. (0.1 mm.); 2,4-dinitrophenylhydrazone m.p. 146°-148°C.

Analysis for: C₂₀ H₂₁ N₄ O₄ Br ; Calculated: C, 52.07; H, 4.59; N,12.14; Br, 17.32; Found: C, 51.87; H, 4.64; N, 11.97; Br, 17.12.

EXAMPLE III 1-(3-Bromopropyl)-1-Methyl-7-Methoxy-2-Tetralone

Using a procedure analogous to that described in Example II for thepreparation of 1-(3-bromopropyl-1-methyl)-2-tetralone there is obtainedfrom 1-methyl-7-methoxy-2tetralone (11.4 g.) and 1,3-dibromopropane (24ml.), 6.7 g. of the title product, b.p. 135°-145° C. (1 mm.).

I. r. analysis: 5.8, 8.0 μ.

EXAMPLE IV 1-(5-Bromopentyl)-1-Methyl-2-Tetralone

Using a procedure analogous to that described in Example I for thepreparation of 1-(4-chlorobutyl)-1-methyl-7-methoxy-2-tetralone there isobtained from 1-methyl-2-tetralone (20.0 g., 0.125 mole),1,5-dibromopentane (115.0 g., 0.5 mole), and sodium hydride (6.06 g.,0.1375 mole of a 54.5% dispersion in mineral oil) in dimethylformamide(100 ml.), 19.8 g. (54%) of the title product b.p. 155°-175° C. (0.3mm.).

I. r. analysis: 3.45, 5.85 μ.

EXAMPLE V 1-(5-Bromopentyl)-1-Methyl-7-Methoxy-2-Tetralone

Using a procedure analogous to that described in Example I for thepreparation of 1-(4-Chlorobutyl)-1-methyl-7-methoyx-2-tetralone there isobtained from 1-methyl-7-methoxy-2-tetralone (150.0 g., 0.788 mole),1,5-dibromopentane (707 g., 3.06 mole), and sodium hydride (37.1 g.,0.842 mole of a 54.5% dispersion in mineral oil) in dimethylformamide(600 ml.). 182 g. (68.1% of the title product b.p. 185°-198° C. (1.0mm.).

I. r. analysis: 3.5, 5.80, 7.9 μ.

EXAMPLE VI 1-(4-Chlorobutyl)-1-Ethyl-7-Methoxy-2-tetralone

A. Using a procedure analogous to that described in Example I for thepreparation of 1-(4-chlorobutyl)-1-methyl-7-methoxy-2-tetralone there isobtained from 35 g. of 1-ethyl-7-methoxy-2-tetralone; 37.4 g. of thetitle product b.p. 160°-173° C. (0.4 mm.).

I. r. analysis: 5.83, 8.0 μ.

B. Clean sodium pellets (2.3 g.) are dissolved, while stirringmagnetically under N₂, in absolute ethanol (50 ml.). After cooling to20°-25° C. 1-ethyl-7-methoxy-2-tetralone (20.5 g.) in dry ethanol (50ml.) is added over a period of 30 minutes. After stirring 30 minutesthis solution is added dropwise to a stirred solution of1,4-dibromobutane (44.0 g.) in dry ethanol (60 ml.) while maintainingthe temperature at 10°-15° C. After stirring four hours at thistemperature the reaction is allowed to warm to 20°-25° C. whilecontinuing to stir an additional 12 hours. After chilling below roomtemperature precipitated solids are removed by filtration with aid ofdiatomaceous earth. Concentration of the filtrate under reducedpressure, partitioning the residue so obtained between ether and water,washing the ether layer with saline, drying, concentrating under reducedpressure and distilling under vacuum gives the title product (16 g.) b.p. 165°-175°(0.2 mm.).

EXAMPLE VII 1-(4-Chlorobutyl)-1-Methyl-5-Methoxy-2-Tetralone

Using a procedure analogous to that described in Example I for thepreparation of 1-(4-chlorobutyl)-1-methyl-7-methoxy-2-tetralone there isobtained from 1-methyl-5-methoxy-2-tetralone (45 g.), 40.5 g. of thetitle product, b.p. 150-160° C. (0.15 mm.).

I. r. analysis: 5.82, 7.9 μ.

Example VIII 1-(4-Chlorobutyl)-1-Methyl-6-Methoxy-2-Tetralone

Using a procedure analogous to that described in Example I for thepreparation of 1-(4-chlorobutyl)-1-methyl-7-methoxy-2-tetralone there isobtained from 1-methyl-6-methoxy-2-tetaralone (36 g.) and tetramethylenechlorobromide (140 g.), 30.5 g. of the title product, b. p. 165°-175° C.(0.4 mm.).

I. r. analysis: 5.85, 8.0 μ.

EXAMPLE IX

To prepare: 1-benzyl-1-(4-chlorobutyl)-2-tetralone react1-benzyl-2-tetralone with 1-bromo-4-chlorobutane as taught in Example I.

To prepare: 1-benzyl-1-(4-chlorobutyl)-7-methoxy-2-tetralone react1-benzyl-7-methoxy-2-tetralone with 1-bromo-4-chlorobutane as taught inExample I.

EXAMPLE X6,7,8,9,10,11-Hexahydro-3-Methoxy-5-Methyl-5,10-Methano-5H-Benzocyclononen-12-One

To a two liter reaction vessel, fitted with with a mechanical stirred, adropping funnel, a condenser and drying tube, a thermometer, a nitrogeninlet and a soft rubber stopper is introduced sodium hydride (13 g.,0.27 mole of 50% dispersion in mineral oil) which is then washed withbenzene to remove the mineral oil. Dimethylformamide (750 ml.) is thenadded and 1-(4-chlorobutyl)-1-methyl-7-methoxy-2-tetralone (62.5 g.,0.22 mole in dimethyl formamide (150 ml.) is added dropwise, whilestirring vigorously and maintaining the temperature between 30° and 35°C. The reaction is stirred and heated to 80° to 85° C. for 25 hours,stirred at room temperature overnight and poured into ice water (2.0liter). After acidification with hydrochloride acid (concentrated) theoil which separates is extracted into ether. The extract is washed withsaturated saline and dried over sodium sulfate. The solvent is removedunder reduced pressure and the residue distilled to give the titleproduct (32.5 g.), b.p. 130° to 135° C. (0.25 mm).

I. r. analysis: 5.8, 8.0 μ.

EXAMPLE XI5,6,7,8,9,10-Hexahydro-3-Methoxy-5-Methyl-5,9-Methano-Benzocycloocten-11-One

Using a procedure analogous to that described in Example X for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocycloocten-12-onethere is obtained from 1-(3-bromopropyl)-1-methyl-7-methoxy-2-tetralonein 74% yield the title product, b.p. 118° to 121° C. (0.05 mm.). Asample is converted to the semicarbazone, m.p. 223° to 225° C.

Analysis for: C₁₆ H₂₁ N₃ O₂ ; Calculated: C, 66.87; H, 7.37; N, 14.62;Found: C, 66.73; H, 7.51; N, 14.74.

EXAMPLE XII 5,6,7,8,9,10-Hexahydro-5-Methyl-5,9-Methanobenzocycloocten-11-One

Using a procedure analogous to that described in Example X for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-onethere is obtained from 1-(3-bromoprpoyl)-1-methyl-2-tetralone (4.0 g.)treated with sodium hydride (1 g.); 1.4 g. of the title product, b. p.122° to 130° C. . (0.1 mm.). A sample is converted to the semicarbazoneand crystallized from acetonitrile, m.p. 250° to 251° C.

Analysis for: C₁₅ H₁₉ N₃ O; Calculated: C, 70.00; H, 7.44; N, 16.33;Found: C, 70.30; H, 7.39; N, 16.48.

EXAMPLE XIII5-Methyl-5,6,7,8,9,10,11,12-Octahydro-5,11-Methano-Benzocyclodecen-13-One

Using a procedure analogous to that described in Example X for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-onethere is prepared from 1-methyl-1-(5-bromopentyl)-2-tetralone (19.8 g.,0.0675 mole) and sodium hydride (3.57 g., 0.081 mole, of a 54.5%dispersion in mineral oil) in dimethylformamide (250 ml.); 6.2 g.(40.4%) of the title product, b.p. 126° to 135° C. (0.3 mm.).

I. r. analysis: 3.45, 5.9 μ.

EXAMPLE XIV5-Methyl-3-Methoxy-5,6,7,8,9,10,11,12-Octahydro-5,11-Methano-Benzocyclodecen-13One

A. Using a procedure analogous to that described in Example X for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-onethere is obtained from 1-methyl-1-(5-bromopentyl)-7-methoxy-2-tetralone(90.0 g., 0.264 mole), and sodium hydride (12.87 g., 0.292 mole, of54.5% dispersion in mineral oil) in dimethylformamide (750 ml.); 42.7 g.(62.4%) of the title product, b.p. 150° to 175° C. (0.5 mm.).

I. r. analysis: 3.0, 3.4, 5.9, 8.01 μ.

B. Oil-free sodium hydride (5.28 g.) in benzene (50 ml.) is added to astirred mixture of 1,5-dibromopentane (184 g.) and1-methyl-7-methoxy-2-tetralone (32 g.) in dry benzene (300 ml.).Stirring is continued for 12 hours at 25° and at reflux for anadditional 15 hours. The mixture is cooled, sodium hydride (5.8 g.) in50 ml. benzene added, stirring continued at 25° for 10 hours, and atreflux for 12 additional hours. After cooling excess base is neutralizedwith concentrated hydrochloric acid and the inorganic solids whichprecipitate are removed by filtration. Washing and filtrate with saline,drying over sodium sulfate, concentrating and vaccum distilling gives anoil (21 g.), b.p. 160°-190° C. (0.5 mm.) containing 6.5 g. (27%) of thetitle product by vapor phase chromatography (3% OVI, C200-225-250).

EXAMPLE XV6,7,8,9,10,11-Hexahydro-2-Methoxy-5Methyl-5,10-Methano-5H-Benzocyclononen-12-One

Using a procedure analogous to that described in Example X for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,there is obtained from 30.5 g. of1-(4-chlorobutyl)-1-methyl-6-methoxy-2-tetralone 15 g. of the titleproduct, b. p. 140° to 145° C. (0.5 mm.).

I. r. analysis: 5.82, 8.05 μ.

EXAMPLE XVI6,7,8,9,10,11-Hexahydro-1-Methoxy-5-Methyl-5,10-Methano-5H-Benzocyclononen-12-One

Using a procedure analogous to that described in Example X for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,there is obtained from 40.5 g. of1-(4-chlorobutyl)-1-methyl-5-methoxy-2tetralone, 21.5 g. of the titleproduct, b.p. 130° to 135° C. (0.3 mm.).

I. r. analysis: 5.78, 7.9 μ.

EXAMPLE XVII5-Ethyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-5,10-Methano-5H-Benzocyclononen-12-One

Using a procedure analogous to that described in Example X for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-onethere is obtained from 37.4 g. of1-(4-chlorobutyl)-1-ethyl-7-methoxy-2-tetralone, 22.2 g. of the titleproduct, b.p. 138° 142° C. (0.35 mm.).

I. r. analysis: 5.85, 8.0 μ

EXAMPLE XVIII

To prepare:6,7,8,9,10,11-hexahydro-5-benzyl-5,10-methano-5H-benzocyclononen-12-one,treat 1-benzyl-1-(4-chlorobutyl)-2-tetralone with sodium hydride astaught in Example X.

To prepare:5-benzyl-3-methoxy-6,7,8,9,10,11-hexahydro-5,10-methano-5H-benzocyclononen-12-one,treat 1-benzyl-1-(4-chlorobutyl)-7-methoxy-2-tetralone with sodiumhydride as taught in Example X.

EXAMPLE XIX6,7,8,9,10,11-Hexahydro-3-Methoxy-5-Methyl-5,10-Methano-5H-Benzocyclononen-12-One,Oxime

A.6,7,8,9,10,11-Hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one(0.2 g.), hydroxylamine hydrochloride (0.5 g.) 5% sodium hydroxide (6ml.) and ethanol (2 ml.) are heated at reflux for 4 hours. The reactionis cooled and diluted with water. The supernatant is decanted from theoil which separates. The oil is washed several times with water and isthen treated with 2-propanol from which the title product crystallizes,m.p. 174° to 176° C.

Analysis for: C₁₆ H₂₁ NO₂ Calculated: C, 74.1; H, 8.16; N, 5.40; Found:C, 74.38; H, 8.10; N, 4.98.

I. r. anaylsis: 3.2, 6.2, 8.1 μ.

B. Hydroxylamine hydrochloride (14 g., 0.2 mole) in methanol (250 ml.)is mixed with sodium acetate (165 g., 0.2 mole) in methanol (200 ml.).After standing one hour the solution is filtered and to it is added6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one(10 g., 0.04 mole). The solution is heated under reflux 5 hours,concentrated in volume to approximately 200 ml. Cooling, filtration,washing with methanol and drying gives the title product (8.0); m.p.174° to 176° C.

C. 6,7,8,9,10,11-Hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one (20.0 g., 0.082 mole), and hydroxylaminehydrochloride (28.5 g., 0.410 mole) in pyridine (150 ml.) are stirred atreflux for 24 hours. The mixture is cooled and concentrated. The residueis extracted with ether (750 ml.) in several portions and the extractsare successively washed with water, dilute hydrochloric acid, water andsaline solution, then dried over anhydrous magnesium sulfate, thesolvent removed in vacuo and the residue crystallized from boilingisopropanol to give the title product (6.0 g.), m.p. 167° to 171° C. Asecond crop was obtained, 1.08 g. Total yield is 33%.

EXAMPLE XX5-Methyl-5,6,7,8,9,10,11,12-Octahydro-5,11-Methano-Benzocyclodecen-13-One,Oxime

Using a procedure analogous to that described in Example XIX, Method C,for the preparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,oxime there is obtained from5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methano-benzocyclodecen-13-one(3.9 g., 0.0171 mole) and hydroxylamine hydrochloride (8.55 g., 0.123moles) in pyridine (20 ml.), after recrystallization from isopropanol,1.27 g. of the title product, m.p. 122°-127°.

I. r. analysis: 3.15, 3.45, 6.1 μ.

EXAMPLE XXI5,6,7,8,9,10-Hexahydro-3-Methoxy-5-Methyl-5,9-Methano-Benzocycloocten-11-One,Oxime

By a procedure analogous to that described in Example XIX, Method A, forthe preparation of 6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-5H-benzocyclononen-12-one, oxime there is obtainedfrom5,6,7,8,9,10-hexahydro-3-methoxy-5-methyl-5,9-methanobenzocycloocten-11-one(0.5 g.) and hydroxylamine hydrochloride (6.5 g.), 3.9 g. of productafter trituration with hexane, m. p. 138°-142° C. Recrystallization fromisopropanol-water gives the title product, m.p. 146°-148° C.

Analysis for: C₁₅ H₁₉ NO₂ Calculated: C, 73.44; H, 7.81; N, 5.71; Found:C, 73.11; H, 8.03; N, 5.61.

EXAMPLE XXII5-Methyl-3-Methoxy-5,6,7,8,9,10,11,12-Octahydro-5,11-Methano-Benzocyclodecen-13-One,Oxime

Using a procedure analogous to that described in Example XIX, Method Cfor the preparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,oxime there is obtained from5-methyl-5,6,7,8,9,10,11-octahydro-5,11-methano-benzocyclodecen-13-one(42.6 g., 0.165 mole), and hydroxylamine hydrochloride (57.3 g., 0.824mole) in pyridine (300 ml.); 18.9 g. (42% ) of the title product, m.p.152°-158° C.

Analysis for: C₁₇ H₁₃ N₂ O₂ ; Calculated: C, 74.69; H, 8.48; N, 4.12;Found: C, 75.25; H, 8.64; N, 4.72.

EXAMPLE XXIII6,7,8,9,10-Hexahydro-2-Methoxy-5-Methyl-5,10-Methano-5H-Benzocyclononen-12-One,Oxime

Using a procedure analogous to that described in Example XIX, Method B,for the preparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,oxime there is obtained from 11.5 g. of6,7,8,9,10,11-hexahydro-2-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12one(5.0 g.) of the title product, m.p. 130°-135° C.

I. r. analysis: 3.1; 6.0 μ.

EXAMPLE XXIV6,7,8,9,10,11-Hexahydro-1-Methoxy-5-Methyl-5,10-Methano-5H-Benzocyclononen-12-One,Oxime

Using a procedure analagous to that described in Example XIX, Method B,for preparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,oxime there is obtained from 21.5 g. of6,7,8,9,10,11-hexahydro-1-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,10.9 g. of the title product, m.p. 154°-160° C.

I. r. analysis: 3.1-3.2; 6.0 μ.

EXAMPLE XXV5-Ethyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-5,10-Methano-5H-Benzocyclononen-12-One,Oxime

Using a procedure analogous to that described in Example XIX, Method C,for the preparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,oxime there is obtained from5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one(3.5 g.) and 20 ml. of hydroxylamine hydrochloride (3.5 g.) of the titleproduct as a brown oil which crystallizes on standing.

I. r. analysis: 3.2; 6.0 μ.

Crystallization of the crude solid from ethanol water gives the titleproduct, m.p. 114°-116° C.

Analysis for: C₁₇ H₂₃ NO₂ ; Calculated: C, 74.69; H, 8.48; N, 5.12;Found: C, 75.20; H, 8.93; N, 4.84.

EXAMPLE XXVI

To prepare: 6,7,8,9,10,11-hexahydro-5-benzyl-5,10-methano-5H-benzocyclononen-12-one, oxime treat6,7,8,9,10,11-hexahydro-5-benzyl-5,10-methano-5H-benzocyclononen-12-onewith hydroxylamine hydrochloride as taught in Example XIX, Method C.

To prepare:5-benzyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one,oxime treat 5-benzyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one withhydroxylamine hydrochloride as taught in Example XIX, Method C.

EXAMPLE XXVII6,7,8,9,10,11-Hexahydro-3-Methoxy-5-Methyl-5,10-Methano-5H-Benzocyclononen-12-Amine

A.6,7,8,9,10,11-Hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,oxime (15 g. 0.058 m.) Raney nickel (3 tsps.) ethanol (100 ml.) andconcentrated ammonium hydoxide (50 ml.) are shaken with hydrogen at 45psi and 45° C. The catalyst is removed by filtration and the filtrateconcentrated to remove solvent. The residue is distilled under reducedpressure to afford the title product (11 g.), b.p. 140°-142° C. (0.2mm.) HCl salt, m.p. 298°-299° C.

Analysis for: C₁₆ H₂₄ CINO; Calculated: C, 68.21; H, 8.58; N, 4.96;Found: C, 67.96; H, 8.63; N, 4.92.

B. Undistilled6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine(31 g.) in dry ether (200 ml.) is treated with dry hydrogen chloride inether until the solution is acidic. The precipitated salt is collected,washed with ether and dried to afford a product (32 g.), m.p. 257°-267°C.

This product is dissolved in water (1,000 ml.) and methanol (180 ml.).Addition of concentrated hydrochloric acid (2 ml.), concentration atatmospheric pressure to 500 ml., collection of the precipitate obtainedon cooling, followed by washing and drying gives a product (20.0 g.),m.p. 302°-305° C. On the basis of infrared and nuclear magneticresonance spectra this product is assigned the structure6,7,8,9,10,11-hexahydro-3-methoxy-5α-methyl-5,10-methano-5H-benzocyclononen-12β-amine,hydrochloride.

Concentration of the mother liquors obtained after isolation of theβ-amine product gives a product (2 g.), m.p. 262°-273° C. Furtherconcentration to about 65 ml. clarifying and chilling gives crystals(5.9 g.), m.p. 231°-236° C. which are collected with the aid ofadditional cold water (50 ml.). Recrystallization is accomplished bydissolving in acetone-methanol (2:1), concentrating to one-half volumethen making up to the original volume with acetone. Repetition of theconcentration-dilution process three additional times followed bychilling gives a product (4.5 g.), m.p. 237°-240° C.

Analysis for: C₁₆ H₂₄ ClNO; Calculated: C, 68.21; H, 8.58; N, 4.96; Cl,12.54; Found: C, 68.40; H, 8.72; N, 5.02; Cl, 12.04

On the basis of infrared and nuclear magnetic resonance spectra thisproduct is assigned the structure6,7,8,9,10,11-hexahydro-3-methoxy-5α-methyl-5,10-methano-5H-benzocyclononen-12α-amine, hydrochloride.

EXAMPLE XXVIII6,7,8,9,10,11-Hexahydro-2-Methoxy-5α-Methyl-5,10-Methano-5H-Benzocyclononen-12β-Amine

Using a procedure analogous to that described in Example XXVIIA forpreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine,there is obtained from 5.0 g. of6,7,8,9,10,11-hexahydro-2-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,oxime 2.8 g. of the title product as its hydrochloride, m.p. 284°-287°C.

Analysis for: C₁₆ H₂₄ NOCl; Calculated: C, 68.21; H, 8.58; N, 4.96;Found: C, 68.09; H, 8.85; N, 4.96.

EXAMPLE XXIX6,7,8,9,10,11-Hexahydro-1-Methoxy-5α-Methyl-5,10-Methano-5H-Benzocyclononen-12β-Amine

Using a procedure analogous to that described in Example XXVIIA forpreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-aminethere is obtained from 10.5 g. of6,7,8,9,10,11-hexahydro-1-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one,oxime 7.4 g. of the title product as the hydrochloride, m.p. 308°-309°C.

Analysis for: C₁₆ H₂₄ NOCl Calculated: C, 68.21; H, 8.58; N, 4.96;Found: C, 68.12; H, 8.60; N, 4.84.

EXAMPLE XXX 5α-Methyl-5,6,7,8,9,10,11,12-octahydro-5,11-Methano-Benzocyclodecen-13β-Amine

5-Methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methano-5H-benzocyclodecen-13-one,oxime (2.5 g.), Raney nickel (2 g.), ammonium hydroxide (4 ml.) andethanol (50 ml.) are shaken with hydrogen at 45 psi. After hydrogenuptake ceases (approximately 7 pounds versus 14 pounds theory) thesolution is removed from the apparatus, filtered, and concentrated. Theresidue (pink oil) is combined with fresh Raney nickel, ammoniumhydroxide, and ethanol and hydrogenated at 50 psi and 50°-60° C. Whencompleted the solution is worked up as above. The residue, a colorlessoil, is converted to the hydrochloride salt, filtered, washed, anddried. The salt is recrystallized from water to give the title compound,as the hydrochloride, 1.15 g., m.p. >335° C.

Analysis for: C₁₆ H₂₄ ClN; Calculated: C, 72.29; H, 9.10; N, 5.27;Found: C, 72.12; H, 9.45; N, 5.28.

EXAMPLE XXXI6,7,8,9,10,11-Hexahydro-5α-Methyl-5,10-Methano-5H-Benzocyclononen-12.beta.-Amine

6,7,8,9,10,11-Hexahydro-5-methyl-5,10-methano-5H-benzocyclononen-12-one,oxime (2.5 g.), Raney nickel catalyst (6 g.) in 25 ml. of concentratedammonium hydroxide and 50 ml. of ethanol are shaken with hydrogen at 50psi and 45° C. After hydrogen uptake stops the catalyst is filtered off,the filtrate concentrated, and the residue converted to thehydrochloride salt (2.8 g.); recrystallization from water gives thetitle product as its hydrochloride, m.p. >315° C.

Analysis for: C₁₅ N₂₂ ClN Calculated: C, 71.62; H, 8.81; N, 5.53; Found:C, 71.62; H, 8.81; N, 5.86.

EXAMPLE XXXII5-Ethyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-5,10-Methano-5H-Benzocyclononen-12-Imine

Using a procedure analogous to that described in Example XXVIIA for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-aminethere is obtained from 3.5 g. of5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one,oxime 1.6 g. of the title product, b.p. 150°-160° C. (0.5 mm.).

I. r. analysis: 6.1 μ.

Addition of ethereal hydrogen chloride to the title product in ethergives the hydrochloride salt, m.p. 252°-255° C. (dec).

Analysis for: C₁₇ H₂₄ NOCl; Calculated: C, 69.48; H, 8.23; N, 4.77;Found: C, 69.25; H, 8.28; H, 4.72.

EXAMPLE XXXIII5-Ethyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-5,10-Methano-5H-Benzocyclononen-12-Amine

A. Using a procedure analogous to that described in Example XXVIIA forthe preparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-aminethere is obtained from5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-imine(4.0 g.) approximately 3.5 g. of title product which is converted to itssolid hydrochloride salt, m.p. 226°-231° C.

On the basis of infrared and nuclear magnetic resonance spectra thisproduct is assigned the structure 5α-ethyl- 6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methanol-5H-benzocyclononen-12β-amine,hydrochloride.

Analysis for: C₁₇ H₂₆ NOCL; Calculated: C, 69.01; H, 8.86; N, 4.73;Found: C, 68.76; H, 8.94; N, 4.72.

B. Using a procedure analogous to that described in Example XXVIIA forthe preparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine,from5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one,oxime there is obtained distilled title product which is shown by gaschromatography-mass spectra data to be approximately a 8 to 1 mixture ofepimeric amines. Dissolving 70 g. of this mixture in 1100 ml. of diluteaqueous hydrochloric acid, filtering the solution through diatomaceousearth and allowing it to stand 1 day at room temperature and for 2 daysat 10° gives 64 g. of the hydrogen chloride, hydrate salt of5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12β-aminewith m.p. 253°-256°.

Analysis for: C₁₇ H₂₅ NO . NCl . H₂ O; Calculated: C, 65.05; H, 8.99; N,4.46; Found: C, 65.26; H, 9.01; N, 4.50.

C. The filtrate recovered from B above is made basic with aqueous sodiumhydroxide, extracted with ether and the ether extracts dried andconcentrated to an oil. This oil is chromatographed on 300 g. of silicagel. Elution with a solution of 3 parts benzene, 1 part chloroform gives3.0 g. of pure 5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12α-amine.Conversion of the amine to its hydrogen chloride salt in ether gives acrystalline salt with m.p. 182°-185°.

Analysis for: C₁₇ H₂₆ NOCl; Calculated: C, 69.01; H, 8.86; N, 4.73;Found: C, 68.73; H, 8.91; N, 4.75

EXAMPLE XXXIV5,6,7,8,9,10,-Hexahydro-3-Methoxy-5-Methyl-5,9-Methano-Benzocycloocten-11-Amine

A. Using a procedure analogous to that described in Example XXVIIA forthe preparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-aminethere is obtained from5,6,7,8,9,10-hexahydro-3-methoxy-5-methyl-5,9-methano-benzocycloocten-11-one,oxime (4.2 g.), 2.7 g. of the title compound, b.p. 125°-129° C. (0.1mm.).

A sample is converted to the hydrochloride salt which crystallizes fromethanol: ether, m.p. 262°-264° C.

Analysis for: C₁₅ H₂₂ ClNO; Calculated: C, 67.27; H, 8.28; N, 5.23;Found: C, 67.16; H, 8.48; H, 5.14.

B. Using a procedure analogous to that described in Example XXVIIA forthe preparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine,from5,6,7,8,9,10-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclooctene-11-one,oxime, there is obtained distilled title product which is shown by gaschromatography, mass spectral data to be a 3 to 2 mixture of aminoepimers. By repeated recrystallization of hydrogen chloride salt of 27g. of the epimeric amine mixture from ethanol-ether, there is obtained16.3 g. of product, m.p. 270°-272°, which is assigned the structure5,6,7,8,9,10-hexahydro-3-methoxy-5α-methyl-5,9-methano-benzocycloocten-11α-amine,hydrochloride.

Analysis for: C₁₅ H₂₂ NOCl; Calculated: C, 67.27; H, 8.28; N, 5.23;Found: C, 67.17; H, 8.48; N, 5.14.

C. Concentration of the combined mother liquors from B gives a residuewhich is crystallized from acetonitrile and then repetitivelyrecrystallized from ethanol ether to give a product, m.p. 300°-302°,which is assigned the structure5,6,7,8,9,10-hexahydro-3-methoxy-5α-methyl-5,9-methano-benzocycloocten-11β-amine,hydrochloride.

Analysis for: C₁₅ H₂₂ NOCl; Calculated: C, 67.27; H, 8.28; N, 5.23;Found: C, 67.14; H, 8.24; N, 5.24.

EXAMPLE XXXV3-Methoxy-5α-Methyl-5,6,7,8,9,10,11,12-Octahydro-5,11-Methano-Benzocyclodecen-13β-Amine

Using a procedure analogous to that described in Example XXX for thepreparation of5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methano-benzocyclodecen-13-aminethere is obtained from3-methoxy-5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzocyclodecen-13-one,oxime (18.5 g.) Raney nickel (3 tablespoons), 100 ml. of ethanol and 50ml. of concentrated ammonium hydroxide; after distillation 11.1 g. [b.p.140°-145° C. (1.2 mm.)] of the title product which is converted to thehydrochloride salt which recrystallizes from water, m.p. 311°-312° C.

Analysis for: C₁₇ H₂₆ ClNO; Calculated: C, 69.13; H, 8.86; N, 4.73;Found: C, 69.17; H, 9.16; N, 4.70.

EXAMPLE XXXVI

To prepare:6,7,8,9,10,11-hexahydro-5-benzyl-5,10-methano-5H-benzocyclononen-12-amine(hydrochloride salts, m.p. 154°-158° C. reduce6,7,8,9,10,11-hexahydro-5-benzyl-5,10-methano-5H-benzocyclononen-12-one,oxime as taught in Example XXVII.

To prepare:5-benzyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-amine(hydrochloride salt, m.p. 152°-156° C.) reduce5-benzyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one, oxime as taught in Example XXVII.

EXAMPLE XXXVII6,7,8,9,10,11-Hexahydro-3-Methoxy-N,5α-Dimethyl-5,10-Methano-5H-Benzocyclononen-12β-Amine

6,7,8,9,10,11-Hexahydro-3-methoxy-5α-methyl-5,10-methano-5H-benzocyclononen-12α-amine,hydrochloride (2.5 g.), saturated aqueous sodium bicarbonate (50 ml.),methylene chloride (50 ml.) and ethylchloroformate (3 ml.) are stirred,at room temperature, for 4 hours. The organic layer is separated, washedsuccessively with aqueous sodium carbonate, hydrogen chloride and sodiumchloride, dried and concentrated to give 2.6 g. of oil. This oil isadded to a mixture of 1 g. of lithium aluminum hydride intetrahydrofuran and the resulting mixture is refluxed overnight. Two ml.of water is added and the mixture is filtered. Concentration of thefiltrate gives 2.1 g. of oil which is converted to 1.8 g. of hydrogenchloride salt with m.p. 249°-250° after recrystallization fromethanol-ether.

Analysis for: C₁₇ H₂₆ NOCl; Calculated: C, 69.01; H, 8.86; N, 4.73;Found: C, 68.53; H, 9.08; N, 5.13.

EXAMPLE XXXVIII6,7,8,9,10,11-Hexahydro-3-Methoxy-N,N,5α-Trimethyl-5,10-Methano-5H-Benzocyclononen-12α-Amine

In a manner analogous to that described in Example XXXVII for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclononen-12α-amine, from 1.2 g. of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclononen-12α-aminethere is obtained 0.90 g. of the hydrogen chloride salt of the titleproduct with m.p. 200°-202°.

Analysis for: C₁₈ H₂₈ NOCl; Calculated: C, 69.76; H, 9.11; N, 4.52;Found: C, 69.28; H, 9.12; N, 4.69.

EXAMPLE XXXIX6,7,8,9,10,11-Hexahydro-3-Methoxy-N,N5α-Trimethyl-5,10-Methano-5H-Benzocyclononen-12β-Amine

In a manner analogous to that described in Example XXXVII for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5.10-methano-5H-benzocyclononen-12α-amine,from 1.2 g. of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclononen-12α-aminethere is obtained 1.0 g. of the hydrogen chloride salt of the titleproduct with m.p. 207°-209°.

Analysis for: C₁₈ H₂₈ NOCl . 1/4H O; Calculated: C, 68.79; H, 9.14; N,4.46; Found: C, 68.83; H, 9.36; N, 4.69.

EXAMPLE XL5α-Ethyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-N-Methyl-5,10-Methano-5H-Benzocyclononen-12β-Amine

In a manner analogous to that described in Example XXXVII for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclononen-12α-amine,from 8.0 g. of5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12β-aminethere is obtained 5.5 g. of the hydrogen chloride salt of the titleproduct with m.p. 282°-284° dec. on recrystallization fromethanol-ether.

Analysis for: C₁₈ H₂₈ NOCl; Calculated: C, 69.76; H, 9.11; N, 4.52;Found: C, 69.29; H, 9.22; N, 4.61.

EXAMPLE XLI5α-Ethyl-6,7,8,9,10,11-Hexahydro-N,N-Dimethyl-3-Methoxy-5,10-Methano-5H-Benzocyclononen-12β-Amine

In a manner analogous to that described in Example XXXVII for thepreparation of 6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclononen-12α-amine, from 4.0 g. of5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-N-methyl-5,10-methano-5H-benzocyclononen-12β-aminethere is obtained 2.65 g. of the hydrogen chloride salt of the titleproduct with m.p. 162°-165° on recrystallization from ethanol-ether.

Analysis for: C₁₉ H₃₀ NOCl; Calculated: C, 70.56; H, 9.34; N, 4.33;Found: C, 70.14; H, 9.30; N, 4.30.

EXAMPLE XLII3-Methoxy-N,5α-Dimethyl-5,6,7,8,9,10,11,12-Octahydro-5,11-Methanobenzocyclodecen-13β-Amine

In a manner analogous to that described in Example XXXVII for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclononen-12α-amine,from 8.0 g. of3-methoxy-5α-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzocyclodecen-13β-aminethere is obtained 5.5 g. of the hydrogen chloride salt of the titleproduct with m.p. 303°-305° dec. on recrystallization fromethanol-ether.

Analysis for: C₁₈ H₂₈ NOCl; Calculated: C, 69.76; H, 9.11; N, 4.52;Found: C, 69.27; H, 8.99; N, 4.66.

Nmr analysis: N-CH₃ signal at δ = 2.48 ppm (free base).

EXAMPLE XLIII3-Methoxy-N,N,5α-Trimethyl-5,6,7,8,9,10,11,12-Octahydro-5,11-Methanobenzocyclodecen-13β-Amine

In a manner analogous to that described in Example XXXVII for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-N,5αdimethyl-5,10-methano-5H-benzocyclononen-12α-amine,from 4.0 g. of3-methoxy-N,5α-dimethyl-5,6,7,8,9,10,11,12-octahydro-methanobenzocyclodecen-13β-aminethere is obtained 2.0 g. of the hydrogen chloride salt of the titleproduct with m.p. 195°-198° on recrystallization from ethanol ether.

Analysis for: C₁₉ H₃₀ NOCl . H₂ O; Calculated: C, 66.74; H, 9.43; N,4.10; Found: C, 66.61; H, 9.39; N, 3.96.

EXAMPLE XLIV5,6,7,8,9,10,-Hexahydro-3-Methoxy-N,5α-Dimethyl-5,9-Methanobenzocyclooctene-11β-Amine

In a manner analogous to that described in Example XXXVII for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclonone-12α-amine, from 1.5 g. of5,6,7,8,9,10-hexahydro-3-methoxy-5α-methyl-5,9-methano-benzocyclooctene-11β-aminethere is obtained 1.2 g. of the hydrogen chloride salt of the titleproduct with m.p. 266°-267°.

Analysis for: C₁₆ H₂₄ NOCl; Calculated: C, 68.19; H, 8.58; N, 4.97;Found: C, 67.88; H, 8.88; N, 4.80.

EXAMPLE XLV5α-Ethyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-N-Methyl-5,10-Methano-5H-Benzocyclononen-12α-Amine

In a manner analogous to that described in Example XXXIX for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclononen-12β-amine,from 1.2 g. of5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12α-aminethere is obtained 0.90 g. of the hydrogen chloride salt of the titleproduct with m.p. 284°-285° dec. on recrystallization fromethanol-ether.

Analysis for: C₁₈ H₂₈ NOCl . 1/4H₂ O; Calculated: C, 68.77; H, 9.14; N,4.46; Found: C, 68.69; H, 9.19; N, 4.42.

EXAMPLE XLVIN-Allyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-5α-Methyl-5,10-Methano-5H-Benzocyclononen-12β-Amine

6,7,8,9,10,11-Hexahydro-3-methoxy-5α-methyl-5,10-methano-5H-benzocyclononen-12β-amine (1.7 g.), allylbromide (0.85 g.),diisopropyl ethyl amine (1.3 g.) and benzene (10 ml.) are heated atreflux for 3 hours. The mixture is cooled, diluted with ether andfiltered. The solvents are removed under reduced pressure and theresidue distilled to give the title product (1.3 g.) , b.p. 144°-146° C.(0.2 mm.). The distilled product is taken up in ether and treated with aslight excess of hydrogen chloride in ether to give the hydrochlorideaddition salt of the title product (1.3 g.), m.p. 200°-202° C.

Analysis for: C₁₉ H₂₈ ClNO; Calculated: C, 70.95; H, 8.74; N, 4.35;Found: C, 70.50; H, 8.77; N, 4.46.

EXAMPLE XLVIIN-Allyl-5,6,7,8,9,10-Hexahydro-3-Methoxy-5α-Methyl-5,9-Methanobenzocyclooctene-11α-Amine

Using a procedure analogous to that described in Example XXXVI for thepreparation ofN-allyl-6,7,8,9,10,11-hexahydro-3-methoxy-5α-methyl-5,10-methano-5H-benzocyclononen-12β-aminethere is obtained from5,6,7,8,9,10-hexahydro-3-methoxy-5α-methyl-5,9-methano-benzocycloocten-11-amine(1.4 g.), 1.3 g. of the title product, b.p. 148°-153° C. (0.3 mm.). Asample is converted to the hydrochloride.

Analysis for: C₁₈ H₂₆ ClNO; Calculated: C, 70.22; H, 8.51; N, 4.55;Found: C, 69.75; H, 8.73; N, 4.47.

EXAMPLE XLVIII6,7,8,9,10,11-Hexahydro-3-Methoxy-5α-Methyl-N-Phenethyl-5,10-Methano-5H-Benzocyclononen-12β-Amine

A mixture of6,7,8,9,10,11-hexahydro-3-methoxy-5α-methyl-5,10-methano-5H-benzocyclononen-12β-amine(2.4 g.), phenethyl bromide (3 g.), and diisopropyl ethylamine (1.3 g.)in xylene (20 ml.) is heated at reflux for 18 hours. After cooling etheris added (100 ml.) and the solid material is filtered off and washedwith ether. The combined filtrate is extracted with dilute hydrochloricacid. The solid residue is dissolved in warm water, and added to theacid extract. The solution is basified with 10% sodium hydroxide and theoily layer which separates is taken into ether. After removal of thesolvent the residue is distilled and the fraction boiling at 190°-198°(0.2 mm.) is collected. This is converted to the hydrochloride salt inether which is recrystallized from i-propanol to give the title productas its hydrochloride salt, m.p. 243°-245° C.

Analysis for: C₂₄ H₃₂ ClNO; Calculated: C, 74.80; H, 8.36; N, 3.63;Found: C, 74.55; H, 8.74; N, 3.55.

EXAMPLE XLIX6,7,8,9,10,11-Hexahydro-3-Methoxy-5α-Methyl-N-(3-Methyl-2-Butenyl)-5,10-Methano-5H-Benzocyclononen-12β-Amine

6,7,8,9,10,11-Hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine(4.5 g.), 3,3-dimethylallylbromide (4.5 g.), diisopropyl ethylamine(5.75 g.) and xylene (60 ml.) are heated at reflux for 4 hours. Themixture is cooled, diluted with ether and filtered. The solvent isremoved under vacuum and the residue is distilled to give the titleproduct (1.2 g.), b.p. 166°-170° C. (0.2 mm.). A sample is converted tothe hydrochloride and recrystallized from ethanol, m.p. 295°-298° C.

Analysis for: C₁₇ H₂₆ ClNO; Calculated: C, 69.01; H, 8.86; N, 4.73;Found: C, 68.90; H, 8.92; N, 4.83.

EXAMPLE L5,6,7,8,9,10-Hexahydro-3-Methoxy-5α-Methyl-N-(3-Methyl-2-Butenyl)-5,9-Methano-Benzocycloocten-11α-Amine

5,6,7,8,9,10-Hexahydro-3-methoxy-5α-methyl-5,9-methano-benzocycloocten-11α-amine(1.4 g.), diisopropylethylamine (1.3 g.), and 1-chloro-3-methyl-2-butene(0.7 g.) are refluxed 7 hours in xylene. The reaction is cooled to roomtemperature, filtered and the filtrate extracted with 2N hydrochloricacid. The aqueous extract is basified and extracted with ether. Theether extract is then washed with water, dried over sodium sulfate,concentrated in vacuo, and the residue distilled under reduced pressureto give the title product (1.5 g.), b.p. 150°-155° C. (0.5 mm.).Treatment of the product in ether with hydrogen chloride gives thehydrochloride, m.p. 166°-169° C.

Analysis for: C₂₀ H₃₀ ClNO; Calculated: C, 71.51; H, 9.00; H, 4.17;Found: C, 71.58; H, 9.09; H, 4.20.

EXAMPLE LI12β-Amino-6,7,8,9,10,11-Hexahydro-5α-Methyl-5,10-Methano-5H-Benzocyclononen-3-Ol

A solution of6,7,8,9,10,11-hexahydro-3-methoxy-5α-methyl-5,10-methano-5H-benzocyclononen-12β-amine(1.19 g.) in 48% hydrobromic acid (15 ml.) is refluxed 30 minutes undernitrogen. The mixture is cooled, diluted with water (50 ml.), filteredand evaporated to dryness under reduced pressure. The residue isdissolved in ethanol (50 ml.) and again taken to dryness. Redissolvingin ethanol (25 ml.), addition of ether (50 ml.), and standing in thecold gives crystals which are recrystallized from i-propanol to give thehydrobromide salt of the title product as the i-propanolate (0.72 g.),m.p. 246°-248° C.

Analysis for: C₁₈ H₃₀ BrNO₂ ; Calculated: C, 58.10; H, 8.07; N, 3.76;Found: C, 57.52; H, 8.71; N, 3.69.

EXAMPLE LII12β-Amino-6,7,8,9,10,11-Hexahydro-5α-Methyl-5,10-Methano-5H-Benzocyclononen-2Ol

Using a procedure analogous to that described in Example LI for thepreparation of12β-amino-6,7,8,9,10,11-hexahydro-5α-methyl-5,10-methano-5H-benzocyclononen-3-olthere is obtained from approximately 1.2 g. of6,7,8,9,10,11-hexahydro-2-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine,1.2 g. of the hydrogen bromide salt of the title product, m.p. 299°-303°C.

Analysis for: C₁₅ H₂₂ BrNO; Calculated: C, 57.69; H, 7.10; N, 4.49;Found: C, 57.53; H, 7.13; N, 4.44.

EXAMPLE LIII13β-Amino-5α-Methyl-5,6,7,8,9,10,11,12-Octahydro-5,11-Methano-Benzocyclodecen-3Ol

3-Methoxy-5α-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methano-benzocyclodecen-13β-amine(3 g.) is refluxed in 60 ml. 48% aqueous hydrobromic acid for our hour.The mixture is poured into ice (100 g.) and stirred. The precipitate isthen filtered off, washed with cold water, then with ether and dried.Recrystallization from water (after treating with activated charcoal)gives the title product, 1.85 g., m.p. 269°-270° C.

Analysis for: C₁₆ H₂₄ BrNO . 1/2H₂ O; Calculated: C, 57.18; H, 7.52; N,3.97; Found: C, 57.22; H, 7.61; N, 4.14.

EXAMPLE LIV12β-Amino-6,7,8,9,10,11-Hexahydro-5α-Methyl-5,10-Methano-5H-Benzocyclononen-1-Ol

Using a procedure analogous to that described in Example LI for thepreparation of 12β-amino-6,7,8,9,10,11-hexahydro-5α-methyl-5,10-methano-5H-benzocyclononen-3-ol, there is obtained fromapproximately 1.6 g. of6,7,8,9,10,11-hexahydro-1-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine,1.75 g. of the hydrogen bromide salt of the title product, m.p.245°-250° C.

Analysis for: C₁₅ H₂₂ BrNO; Calculated: C, 57.69; H, 7.10; N, 4.49;Found: c, 57.40; H, 7.02; N, 4.47.

EXAMPLE LV12β-Amino-6,7,8,9,10,11-Hexahydro-5α-Ethyl-5,10-Methano-5H-Benzocyclononen-3-Ol

A mixture of5α-ethyl-6,7,8,9,10,11-hexahydro-5,10-methano-3-methoxy-5H-benzocyclononen-12β-amine(2.0 g.) and 75 ml. of 48% hydrobromic acid is refluxed for one-halfhour, then concentrated to a viscous oil. The oil is dissolved in waterand treated with concentrated aqueous ammonia. Filtration gives 1.7 g.of a crude product, m.p. 170°-191° C. Recrystallization from ethylacetate gives the title product, m.p. 202°-204° C.

Analysis for: C₁₆ H₂₃ NO; Calculated: C, 78.32; H, 9.45; N, 5.71; Found:C, 77.93; H, 9.68; N, 5.88.

EXAMPLE LVI11α-(Dimethylamino)-5,6,7,8,9,10-Hexahydro-5α-Methyl-5,9-Methano-Benzocycloocten-3-Ol

5,6,7,8,9,10-Hexahydro-3-methoxy-N,N,5α-trimethyl-5,9-methano-benzocycloocten-11α-amine(1.2 g.) is refluxed for one hour under a dry nitrogen atmosphere in 13ml. of aqueous 48% hydrobromic acid. Concentration of the solutionaffords a residue which on recrystallization from ethanol-ether givesthe title product as its hydrobromic acid salt, m.p. 268°-271° C.

Analysis for: C₁₆ H₂₄ NOBr; Calculated: C, 58.89; N, 7.41; N, 4.29;Found: C, 58.80; N, 7.52; N, 4.22.

EXAMPLE LVII11α-Amino-5,6,7,8,9,10-Hexahydro-5α-Methyl-5,9-Methanobenzocycloocten-3-Ol

In a manner analogous to that described in Example LI for thepreparation of12β-amino-6,7,8,9,10,11-hexahydro-5α-methyl-5,10-methano-5H-benzocyclononen-3-ol,from 2.0 g. of5,6,7,8,9,10-hexahydro-3-methoxy-5α-methyl-5,9-methanobenzocyclooctene-11α-aminethere is obtained 2.3 g. of the hydrogen bromide, ethanolate salt of thetitle product with m.p. 277°-280° on recrystallization fromethanol-ether.

Analysis for: C₁₄ H₂₀ NOBr . 1/2 C₂ H₅ OH; Calculated: C, 56.07; H,7.22; H, 4.36; Found: C, 55.86; H, 7.37; N, 4.10.

EXAMPLE LVIII11β-Amino-5,6,7,8,9,10-Hexahydro-5α-Methyl-5,9-Methanobenzocycloocten-3-Ol

In a manner analogous to that described in Example LI for thepreparation of12β-amino-6,7,8,9,10,11-hexahydro-5α-methyl-5,10-methano-5H-benzocyclononen-3-ol,from 1.25 g. of5,6,7,8,9,10-hexahydro-3-methoxy-5α-methyl-5,9-methanobenzocyclooctene-11β-aminethere is obtained 1.05 g. of the hydrogen bromide salt of the titleproduct with m.p. 305°-310° dec. on recrystallization fromethanol-ether.

Analysis for: C₁₄ H₂₀ NOBr; Calculated: C, 56.38; H, 6.76; N, 4.70;Found: C, 56.01; H, 6.79; N, 4.63.

EXAMPLE LIX12α-Amino-6,7,8,9,10,11-Hexahydro-5α-Methyl-5,10-Methano-5H-Benzocyclononen-3-Ol

In a manner analogous to that described in Example LI for thepreparation of12β-amino-6,7,8,9,10,11-hexahydro-5α-methyl-5,10-methano-5H-benzocyclononen-3-ol,from 1.2 g. of6,7,8,9,10,11-hexahydro-3-methoxy-5α-methyl-5,10-methano-5H-benzocyclononen-12α-aminethere is obtained 1.1 g. of the hydrogen bromide salt of the titlecommpound with m.p. 130°-134° on recrystallization from acetonitrile.

Analysis for: C₁₅ H₂₁ NO . HBr . 1/4 CH₃ CN; Calculated: C, 57.72; H,7.11; N, 5.43; Found: C, 57.47; H, 7.00; N, 5.57.

EXAMPLE LX12α-Amino-6,7,8,9,10,11-Hexahydro-5α-Ethyl-5,10-Methano-5H-Benzocyclononen-3-Ol

In a manner analogous to that described in Example LI for thepreparation of12β-amino-6,7,8,9,10,11-hexahydro-5α-methyl-5,10-methano-5H-benzocyclononen-3-ol,from 1.0 g. of 5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12α-amine, there isobtained 0.72 g. of the hydrogen bromide salt of the title product m.p.266-270° on recrystallization from ethanol-ether.

Analysis for: C₁₆ H₂₄ NOBr; Calculated: C, 58.89; H, 7.41; N, 4.29;Found: C, 58.50; H, 7.47; N, 4.10

EXAMPLE LXI6,7,8,9,10,11-Hexahydro-3-Methoxy-N,5α-Dimethyl-5,10-Methano-5H-Benzocyclononen-12β-Amine

6,7,8,9,10,11-Hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-one(3 g.), calcium oxide (2 g.), and liquid methyl amine (10 ml.) areheated in a sealed vessel at 180°-190° C. for 18 hours. After coolingthe mixture is diluted with ether and filtered to separate the hydratedcalcium oxide. The filtrate is concentrated to an oil which is taken upin ethanol and shaken with hydrogen at 45 psi in the presence ofplatinum dioxide catalyst. The catalyst is removed by filtration, rinsedthoroughly with ethanol and combined filtrate is concentrated in vacuo.The residue was distilled under reduced pressure to give the titleproduct (1.8 g.), b.p. 138°-144° C. (0.2 mm.). For analytical purposes asample is converted to the hydrochloride which crystallizes fromethanol, m.p. 295°-298° C.

Analysis for: C₁₇ H₂₂ CINO; Calculated: C, 69.01; H, 8.86; N, 4.73;Found: C, 68.90; H, 8.92; H, 4.83.

EXAMPLE LXII5,6,7,8,9,10-Hexahydro-3-Methoxy-5α-Methyl-N-Phenethyl-5,9-Methano-Benzocycloocten-11α-Amine

Using a procedure analogous to that described in Example LXI for thepreparation ofN,5α-dimethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12β-aminethere is obtained from5,6,7,8,9,10-hexahydro-3-methoxy-5-methyl-5,9-methanobenzocycloocten-11-one(2.3 g.) 1.80 g. of the title product, b.p. 170°-200° C. (0.5 mm.). Asample is converted to the hydrochloride salt.

Analysis for: C₂₃ H₃₀ CINO; Calculated: C, 74.27; H, 8.12; N, 3.77;Found: C, 74.23; H, 8.29; N, 3.59.

EXAMPLE LXIII5,6,7,8,9,10-Hexahydro-3-Methoxy-N,5α-Dimethyl-5,9-Methano-Benzocycloocten-11α-Amine

Using a procedure analogous to that described in Example LXI for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclononen-12β-aminethere is obtained from5,6,7,8,9,10-hexahydro-3-methoxy-5-methyl-5,9-methano-benzocycloocten-11-one(9.5 g.), 5.4 g. of the title product as the hydrochloride salt, m.p.232°-236° C.

Analysis for: C₁₆ H₂₄ CINO; Calculated: C, 68.19; H, 8.58; N, 4.97,Found: C, 67.83; H, 8.45; N, 4.91.

EXAMPLE LXIVN-Allyl-N,5α-Dimethyl-5,6,7,8,9,10-Hexahydro-3-Methoxy-5,9-Methano-Benzocycloocten-11α-Amine

N-Allyl-5,6,7,8,9,10-hexahydro-3-methoxy-5α-methyl-5,9-methano-benzocycloocten-11α-amine(3 g.), ethylchloroformate (3 ml.), saturated aqueous sodium bicarbonate(50 ml.) and methylene chloride (25 ml.) are stirred vigorouslyovernight at room temperature. The layers are then separated, themethylene chloride washed with 2N hydrochloric acid, dried overpotassium carbonate and concentrated in vacuo. The residue obtained (3.3g.) is dissolved in tetrahydrofuran (100 ml.), stirred and refluxedunder nitrogen with lithium aluminum hydride (1 g.) for 20 hours. Themixture is cooled, water (1.5 ml.) added to destroy excess hydride, andaluminum salts removed by filtration. The filtrate is dried andconcentrated in vacuo and the residue distilled to give the titleproduct (1.4 g.), b.p. 130°-135° C. (0.5 mm.). A portion is dissolved inether, treated with hydrogen chloride, the crystals recovered byfiltration and recrystallized from ethyl acetate to give a hydrochloridesalt, m.p. 164°-166° C.

Analysis for: C₁₉ H₂₈ CINO; Calculated: C, 70.89; H, 8.77; N, 4.35;Found: C, 71.06; H, 9.07; N, 4.53.

EXAMPLE LXV5,6,7,8,9,10-Hexahydro-3-Methoxy-N,N,5-Trimethyl-5,9-Methano-Benzocycloocten-11-Amine

Using a procedure analogous to that described in Example LXIV for thepreparation ofN-allyl-N,5-dimethyl-5,6,7,8,9,10-hexahydro-3-methoxy-5,9-methano-benzocycloocten-11-aminethere is obtained fromN,5-dimethyl-5,6,7,8,9,10-hexahydro-3-methoxy-5,9-methano-benzocycloocten-11-amine(11.1 g.), 8.1 g. of the title product, b.p. 125°-230° C. (0.3 mm.). Theproduct in solution in ether is converted by treatment with hydrogenchloride to a crystalline hydrochloride salt. Recrystallization fromethanol-ether gives a product, A, m.p. 180°-190° which is recrystallizedfrom ethanol-ether to give a product having needle-shaped crystals, m.p.225°-226° C.

Analysis for: C₁₇ H₂₆ CINO; Calculated: C, 69.01; H, 8.86; N, 4.74;Found: C, 68.89; H, 8.92; N, 4.70.

On the basis of infrared and nuclear magnetic resonance spectra thisproduct is assigned the structure5,6,7,8,9,10-hexahydro-3-methoxy-N,N,5α-trimethyl-5,9-methano-benzocyclooctane-11β-amine,hydrochloride.

From the mother liquors remaining after crystallization of product A,after concentration, is obtained a second product, m.p. 218°-223° C.,recrystallization from ethanol-ether gives a product having hexagonalcrystals, m.p. 221°-223° C.

Analysis for: C₁₇ H₂₆ CINO; Calculated: C, 69.01; H, 8.86; N, 4.74;Found: C, 68.89; H, 8.64; N, 4.74.

On the basis of infrared and nuclear magnetic resonance spectra thisproduct is assigned the structure5,6,7,8,9,10-hexahydro-3-methoxy-N,N,5α-trimethyl-5,9-methano-benzocyclooctane-11α-amine,hydrochloride.

EXAMPLE LXVIN,5α-Dimethyl-N-Phenethyl-5,6,7,8,9,10-Hexahydro-3-Methoxy-5,9-Methano-Benzocycloocten-11α-Amine

Using a procedure analogous to that described in Example LXIV for thepreparation ofN-allyl-N,5-dimethyl-5,6,7,8,9,10-hexahydro-3-methoxy-5,9-methano-benzocycloocten-11-aminethere is obtained from5,6,7,8,9,10-hexahydro-3-methoxy-5-methyl-N-phenethyl-5,9-methano-benzocycloocten-11-amine(3.8 g.) 3.1 g. of the title product, b.p. 185°-190° C. (0.3 mm.).Treatment of a portion of the product in acetone with one equivalent offumaric acid gives the fumarate salt which is recrystallized fromacetone as a hydrate, m.p. 149°-151° C.

Analysis for: C₂₈ H₃₅ NO₅ . 1/4 H₂ O; Calculated: C, 71.53; H, 7.61; N,2.98; Found: C, 71.58; H, 7.73; N, 2.98.

EXAMPLE LXVIIN,5α-Dimethyl-5,6,7,8,9,10-Hexahydro-3-Methoxy-N-(3-Methyl-2-Butenyl)-5,9-Methano-Benzocycloocten-11α-Amine

Using a procedure analogous to that described in Example LXIV for thepreparation ofN-allyl-N,5-dimethyl-5,6,7,8,9,10-hexahydro-3-methoxy-5,9-methanobenzocycloocten-11-amine,there is obtained from5,6,7,8,9,10-hexahydro-3-methoxy-5-methyl-N-(3-methyl-2-butenyl)-5,9-methano-benzocycloocten-11-amine(3.6 g.) 2.6 g. of the title product, b.p. 150°-155° C. (0.4 mm.).Treatment of a portion of the product in acetone with fumaric acid givesthe crystalline fumaric acid salt as a hydrate, m.p. 136°-138° C.

Analysis for: C₂₅ H₃₅ NO₅ . 1/4 4H₂ O; Calculated: C, 69.19; H, 8.24; N,3.22; Found: C, 69.20; H, 8.11; N, 3.32.

EXAMPLE LXVIIIN,5α-Dimethyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-N-(3-Methyl-2-Butenyl)-5,10-Methano-5H-Benzocyclononen-12β-Amine

6,7,8,9,10,11-Hexahydro-3-methoxy-5-methyl-N-(3-methyl-2-butenyl)-5,10-methano-5H-benzocyclononen-12-amine(3.5 g.), ethyl chloroformate (6 g.), saturated aqueous sodiumbicarbonate (100 ml.) and methylenedichloride (50 ml.) are stirredvigorously at room temperature for 24 hours. The layers are thenseparated and the organic layer is washed with 2N hydrochloric acid,dried over potassium carbonate and concentrated in vacuo. The residue (3g.) is dissolved in tetrahydrofuran (50 ml.) and added to a suspensionof lithium aluminum hydride in tetrahydrofuran (50 ml.) stirred andheated to reflux for 18 hours. After cooling, water (4.5 ml.) is addedand the reaction mixture is stirred 30 minutes and filtered. Thefiltrate is dried over anhydrous sodium sulfate and concentrated. Theresidue (2 g.) is treated with fumaric acid in acetone to give thefumarate salt of the title product as the hemihydrate (1.8 g.), m.p.108°-110° C.

Analysis for: C₂₆ H₃₇ NO₂ . 1/2 H₂ O; Calculated: C, 69.02; H, 8.47; N,3.08: Found: C, 68.82; H, 8.54; N, 2.94.

EXAMPLE LXIX12β-Amino-6,7,8,9,10,11-Hexahydro-5α-Methyl-5,10-Methano-5H-Benzocyclononen-3-Ol, Acetate

A. A mixture of 12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methano-5H-benzocyclononen-3-ol(15.0 g.), carbobenzyloxy chloride (11.6 g.) and 100 ml. of saturatedaqueous sodium bicarbonate are stirred for 30 minutes. Methylenechloride (100 ml.) is added and the mixture stirred for 1 hour. Theorganic layer is separated, dried and concentrated. The residue istriturated with ethyl acetate and pentane, then filtered to give 24 g.of crude product. Recrystallization from ethyl acetate-cyclohexane gives18.3 g. of carbobenzyloxylated amine with m.p. 103°-110°.

B. A solution of the carbobenzyloxylated amine (5.0 g.) of part A above,acetic anhydride (10 ml.) and pyridine (50 ml.) is allowed to standovernight. The solution is diluted with water and extracted with ether.The ether extracts are washed with 2% aqueous hydrochloric acid, driedand concentrated to give 5.1 g. of o-acetylated product shown to be pureby thin layer chromatography.

C. A solution of the o-acetyl product of part B above (2.5 g.) andhydrogen chloride gas (0.75 g.) in tetrahydrofuran (50 ml.) ishydrogenated in a Parr apparatus over 250 mg. of 10% palladium on carbonunder 40 lbs. of hydrogen pressure for 90 minutes. The catalyst isfiltered and concentration of the filtrate gives 2.2 g. of title productas a viscous glass. Crystallization of the glassy product fromtetrahydrofuran-ether gives crystalline12β-amino-6,7,8,9,10,11-hexahydro-5α-methyl-5,10-methano-5H-benzocyclononen-3-ol,acetate, hydrochloride with m.p. 268° dec.

Analysis for: C₁₇ H₂₄ NO₂ Cl; Calculated: C, 65.90; H, 7.81; N, 4.52;Found: C, 65.38; H, 7.82; H, 4.48.

EXAMPLE LXX12β-Amino-6,7,8,9,10,11-Hexahydro-5α-Methyl-5,10-Methano-5H-Benzocyclononen-3-Ol, Cyclopropane Carboxylate

A. A solution of 2.0 g. of the carbobenzyloxylated amine, described inExample LXIX part A, and 2.0 ml. of cyclopropane carboxoyl chloride in10 ml. of pyridine is allowed to stand overnight. The solution isdiluted with water and extracted with ether. The ether extracts arewashed with 2% aqueous hydrochloric acid, dried and concentrated to anoil. The oil is chromatographed on 70 g. of activity III Woelm alumina.Elution with ether gives 1.5 g. of oil which is crystallized from ethylacetate hexane to give 1.2 g. of O-cyclopropane carboxylate derivativewith m.p. 104°-109°.

B. In a manner analogous to that described in Example LXIX, part C, forthe preparation of12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methano-5H-benzocyclononen-3-ol,acetate, from 1.0 g. of the O-cycloproprane carboxylate derivative ofpart A of above there is obtained 0.45 g. of the hydrogen chloride saltof the title product with m.p. 255°-57° dec. on crystallization fromtetrahydro furan-ether.

Analysis for: C₁₉ H₂₆ NO₂ Cl . 1/4H₂ O; Calculated: C, 67.04; H, 7.83;N, 4.12; Found: C, 66.79; H, 7.68; N, 4.14.

EXAMPLE LXXI Resolution of5α-Ethyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-5,10-Methano-5H-Benzocyclononen-12β-Amine

A solution of5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12β-amine(64.6 g., 0.249 mole) in 300 ml. of methanol is added to a solution of41.5 g. (0.275 mole) of 1-tartaric acid in 1400 ml. of methanol. Theresulting solution is warmed, filtered and diluted to 2000 ml. andallowed to stand for 3 days. Filtration then gives 36.1 g. of salt withm.p. 200°-203° dec. and [α]_(D) = - 27° (1% in dimethyl formamide).Recrystallization of the salt from methanol gives 29.1 g. with m.p.212°-214° and [α]_(D) = - 32.8°. This salt is converted to the free baseby treating it with aqueous sodium hydroxide extracting the aqueousmixture with ether and drying the ether extracts over anhydrouxmagnesium sulfate. On removal of the drying agent and the ether solvent17.6 g. of resolved base is obtained. This is converted to its hydrogenchloride, hydrate salt which has a m.p. 115°-119° dec. and [α]_(D) = -44.1° (2% in methanol).

To obtain the opposite rotating isomer, the mother liquors from thefirst crystallizations of above are concentrated, the residue treatedwith aqueous sodium hydroxide and extracted with ether. On drying theether extracts over anhydrous magnesium sulfate and concentrating theextracts, 41.5 g. of base is obtained. This is dissolved in 500 ml. ofmethanol and the solution is added to a solution of 26.4 g. ofd-tartaric acid in 1000 ml. of methanol. This solution is diluted to1600 ml. and allowed to stand for 5 days. Filtration gives 36.7 g. ofsalt with m.p. 205°-209° dec. and [α]_(D) = + 30.3° (1% indimethylformamide). Recrystallization of this salt from methanol gives30.0 g. of salt with m.p. 209°-211° dec. and [α]_(D) = + 31.9°.Conversion of this salt to free base by the same procedure as for theminus rotating isomer described above gives 16.8 g. of base. This isconverted to its hydrogen chloride hydrate salt which has m.p. 115°-119°dec. and [α]_(D) = + 44.5° (2% in methanol).

EXAMPLE LXXII Preparation of Plus and Minus Rotating Isomers of12β-Amino-6,7,8,9,10,11,-Hexahydro-5α-Ethyl-5,10-Methano-5H-Benzocyclononen-3 -Ol

A. A mixture of optically pure minus rotating5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12β-amine(9.5 g.) and 80 ml. of 48% aqueous hydrobromic acid are heated at thereflux temperature under a dry nitrogen atmosphere for 30 minutes. Theresulting solution is concentrated to 40 ml., diluted to 150 ml. withwater and basified with concentrated aqueous ammonia. After allowing tostand one hour, the mixture is filtered to give 8.9 g. of product withm.p. 185°-192°. Recrystallization of the product from ethyl acetategives 7.5 g. with m.p. 194°-196° and [α]_(D) = - 51.3° (2% in methanol).

B. When optically pure plus rotating5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12β-amine(9.3 g.) is treated with aqueous 48% hydrobromic acid as in A, there isobtained 9.3 g. of crude product with m.p. 178°-190°. Recrystallizationof this from ethyl acetate gives 7.0 g. of product with m.p. 194°-196°and [α]_(D) = + 52.0° (2% in methanol).

EXAMPLE LXXIII

When the following compounds are administered to rats by the routesindicated, for evaluation of analgesic potential by the proceduredescribed hereinabove, they exhibit the effective dose-50 valuestabulated.

    __________________________________________________________________________                     Mode of Effective dose-50                                    Compound        Administration                                                                         (mg/kg body weight)                                  __________________________________________________________________________    6,7,8,9,10,11-hexahydro-3-                                                                    intraperitoneal                                                                        25                                                   methoxy-5α-methyl-5,10-                                                                 oral     30                                                   methano-5H-benzocyclononen-                                                   12β-amine                                                                12β-amino-6,7,8,9,10,11-                                                                 intraperitoneal                                                                        7.5                                                  hexahydro-5α-methyl-5,10-                                                               intramuscular                                                                          1.8                                                  methano-5H-benzocyclononen-                                                                   oral     23                                                   3-ol                                                                          5α-ethyl-6,7,8,9,10,11-                                                                 intraperitoneal                                                                        3.5                                                  hexahydro-3-methoxy-5,10-                                                                     intramuscular                                                                          13.5                                                 methano-5H-benzocyclononen-                                                                   oral     11                                                   12β-amine                                                                12β-amino-6,7,8,9,10,11-                                                                 intraperitoneal                                                                        3.5                                                  hexahydro-5α-ethyl-5,10-                                                                intramuscular                                                                          0.25                                                 methano-5H-benzocyclononen-                                                                   oral     12                                                   3-ol                                                                          3-methoxy-5α-methyl-5,6,7,                                                              intraperitoneal                                                                        4.5                                                  8,9,10,11,12-octahydro-5,11-                                                                  intramuscular                                                                          15                                                   methano-benzocyclodecen-13β-                                                             oral     9                                                    amine                                                                         13β-amino-5α-methyl-5,6,7,8,                                                       intraperitoneal                                                                        1.1                                                  9,10,11,12-octahydro-5,11-                                                                    intramuscular                                                                          0.47                                                 methano-benzocyclodecen-3-ol                                                                  oral     9                                                    (-)-13β-amino-5,6,7,8,9,10,                                                              intraperitoneal                                                                        0.78                                                 11,12-octahydro-5α-methyl-5,                                                            intramuscular                                                                          0.09                                                 11-methano-benzocyclodecen-                                                                   oral     2.0                                                  3-ol                                                                          __________________________________________________________________________

EXAMPLE LXXIV 1-Ethoxycarbonyl-2-Indanone

To a stirred mixture of sodium hydride (126 g. of a 57% suspension innujol), 2000 ml. of benzene and 2 ml. of ethanol heated at its refluxtemperature under dry nitrogen is added dropwise the diethyl ester ofo-phenylene-diacetic acid (335.6 g.) in 700 ml. of benzene. The mixtureis refluxed 1.5 hours, poured into water and extracted with ether. Theether extracts are dried and concentrated to give an oil which iscrystallized from ethanol-water to give 220 g. of the title product withm.p. 58°-61°.

EXAMPLE LXXV 1-(3-Bromopropyl)-1-Ethoxycarbonyl-2-Indanone

To a stirred solution of 1,3-dibromopropane (175 ml.) and ethanol (250ml.) is added dropwise a solution of 1-ethoxy-carbonyl-2-indanone (51g.) and sodium hydroxide (10 g.) in 500 ml. of ethanol and 200 ml. ofwater. The solution is refluxed for 5 hours and cooled. The bottom layeris separated and the upper layer is diluted with water and extractedwith two 100 ml. portions of carbon tetrachloride. The combined lowerlayers were washed with 5% aqueous sodium hydroxide and water thenconcentrated and distilled to give, after a small forecut, the titleproduct (40.3 g.) with b.p. 155°-165° at 0.5 mm.

EXAMPLE LXXVI 1-Ethoxycarbonyl-1,3-Propano-2-Indanone

To a stirred mixture of benzene (400 ml.) and sodium hydride (5.3 g. ofa 57% suspension in nujol), which is free of nujol, is added dropwise,under dry nitrogen, 1-(3-bromopropyl)-1-ethoxy-carbonyl-2-indanone (39.3g.) in 100 ml. of benzene. The mixture is stirred at room temperaturefor 18 hours. Water is added and the organic layer is separated, washedwith aqueous sodium chloride, dried, concentrated and distilled to giveafter a small forecut, 20.5 g. of the title product with b.p. 130°-145°at 0.5 mm.

EXAMPLE LXXVII 1-Ethoxycarbonyl-1,3-Propano-2-Indanone, Oxime

A mixture of hydroxylamine hydrochloride (2.1 g.), sodium acetate (2.5g.), water (10 ml.), ethanol (40 ml.) and1-ethoxycarbonyl-1,3-propano-2-indanone (2.5 g.) is heated quickly toits reflux temperature and kept at reflux for 5 minutes. The mixture isdiluted with water and extracted with ether. The ether extracts aredried and concentrated to give an oil. Chromatography of the oil onactivity III alumina gives, with elution with benzene, 2.0 g. of oilwhich, when triturated with ethyl-acetate-heptane and filtered, gives1.20 g. of the title product with m.p. 118°-119°.

EXAMPLE LXXVIII10-Amino-6,7,8,9,-Tetrahydro-5,9-Methano-5H-Benzocycloheptene-5-Methanol

A mixture of 1-ethoxycarbonyl-1,3-propano-2-indanone oxime (1.9 g.) andlithium aluminum hydride (1.6 g.) and 100 ml. of tetrahydrofuran isheated at its reflux temperature under dry nitrogen for 40 hours andallowed to stand for 3 days at room temperature. A few ml. ofconcentrated aqueous ammonia is added and after 15 minutes stirring themixture is filtered. The filter cake is washed twice with isopropanolcontaining a little ammonia. The combined filtrates are concentrated togive 1.6 g. of oil which when treated with hydrogen chloride in etherand ethanol gives 1.2 g. of crystalline hydrochloride salt of the titleproduct with m.p. 217°-220°.

Analysis for: C₁₃ H₁₈ NOCl Calculated: C, 65.12; H, 7.57; N, 5.84 Found:C, 64.99; H, 7.80; N, 5.73.

EXAMPLE LXXIX5-Methyl-6,7,8,9-Tetrahydro-5,9-Methano-5H-Benzocyclopheptene-10 -Amine

To a cold (5°) mixture of pyridine (50 ml.) and10-amino-6,7,8,9-tetrahydro-5,9-methano-5H-benzocycloheptane-5-methanol,hydrochloride (5.1 g.) is added, in portions, 8.0 g. ofo-tolune-sulfonyl chloride in 20 ml. of pyridine. After keeping on icefor 3 hours, 8.0 g. of p-toluenesulfonyl chloride in 20 ml. of pyridineis again added. The resulting solution is allowed to stand overnightthen is poured into ice water and extracted with ether. The etherextracts are washed with dilute hydrochloric acid, dried andconcentrated to give 11 g. of crude product. Trituration of the crudeproduct with ether and recrystallization from ethyl acetate-heptanegives 8.1 g. of product (A) with m.p. 157°-159°.

Analysis for: C₂₇ H₂₉ NO₅ S₂ Calculated: C, 63.39; H, 5.71; N, 2.74Found: C, 63.33; H, 5.82; N, 2.43.

A mixture of the ditosylate (A) (4.0 g.), lithium aluminum hydride (1.5g.) and tetrahydrofuran is allowed to stir at room temperature for 1hour under nitrogen then is refluxed overnight. Four ml. of water isadded and the mixture is filtered. The collected solid is treated withdilute hydrochloric acid and extracted with ether. The ether extractsare combined with the filtrate of above and concentrated to give an oilysolid (3.4 g.). Crystallization of the solid from ethanol-water gives1.4 g. of product (B) with m.p. 173°-175°.

Analysis for: C₂₀ H₂₃ NO₂ S Calculated: C, 70.36; H, 6.79; N, 4.10Found: C, 70.29; H, 6.65; N, 4.39.

Sodium metal (2.8 g.) is dissolved in a solution of napthalene (15.4 g.)and dimethoxyethane (130 ml.) under a nitrogen atmosphere with stirring.After 1.5 hours, product (B) (4.6 g.), in 45 ml. of dimethoxyethane, isadded and the mixture is stirred for 2 hours. Water (1 ml.) is added andthe mixture concentrated. The residue is dissolved in ether-water andthe ether separated. The ether layer is extracted with dilutehydrochloric acid. The acid layer is basified with concentrated sodiumhydroxide and extracted with ether and dried. Addition of etherealhydrogen chloride gives 2.3 g. of the hydrogen chloride salt of thetitle product with m.p. 225°-227° which is collected by filtration.

Analysis for: C₁₃ H₁₈ NCl . 1/4H₂ O Calculated: C, 68.41; H, 8.16; N,6.14 Found: C, 68.62; H, 8.10; N, 5.92.

EXAMPLE LXXX Resolution of5,6,7,8,9,10,11,12-Octahydro-3-Methoxy-5α-Methyl-5,11-Methanobenzocyclodecen-13β-Amine

Part A

A solution of racemic5,6,7,8,9,10,11,12-octahydro-3-methoxy-5α-methyl-5,11-methanobenzocyclodecen-13β-amine(83 g.) in 200 ml. of methanol is added to a solution of d-tartaric acid(57 g.) in 500 ml. of methanol. The solution is diluted to 1 liter andallowed to stand for 2 days. Filtration gives 83.5 g. of salt with m.p.200°-208° dec. Three recrystallizations of this salt from methanol give21 g. of optically pure tartrate salt with m.p. 213°-215°. This isconverted to optically pure base by treatment of the salt with dilutesodium hydroxide and extraction with ether. Exactly 1/2 of the driedether extracts (225 ml.) are treated with 15 ml. of ethanol andacidified with ethereal hydrogen chloride. Filtration gives 5.8 g. ofthe hydrochloride salt of the plus rotating enantiomorph with m.p.234°-237°.

Analysis for: C₁₇ H₂₆ NOCl [α]_(D) ²⁵ = + 46°. Calculated: C, 69.01; H,8.86; N, 4.73 Found: C, 68.90; H, 9.10; N, 4.42.

Part B

The mother liquors of the tartrate crystallization of above areconcentrated and the residue is converted to base by treatment withdilute aqueous sodium hydroxide and extraction with ether. Removal ofthe ether gives 58 g. of base which is dissolved in methanol and treatedwith 38 g. of 1-tartaric acid in methanol. The final solution has avolume of 800 ml. Filtration after 4 days of standing gives 41.3 g. oftartrate salt with m.p. 204°-209° dec. Two recrystallizations of thissalt give optically pure tartrate salt with m.p. 216°-218°. Conversionto optically pure base and subsequently hydrogen chloride salt as inpart A yields 6.0 g. of hydrochloride salt of the minus rotatingenantiomorph with m.p. 234°-237° and [α]_(D) ²⁵ = - 46.0°.

Analysis for: C₁₇ H₂₆ NOCl Calculated: C, 69.01; H, 8.86; N, 4.73 Found:C, 68.63; H, 9.10; N, 4.35.

EXAMPLE LXXXI(+)-13β-Amino-5,6,7,8,9,10,11,12-Octahydro-5α-Methyl-5,11-Methanobenzocyclodecen-3-Ol

The second half of the ethereal solution of optically pure plus rotatingbase described in Example LXXX, Part A is concentrated to give 6.5 g. ofbase. This is treated with 100 ml. of 48% aqueous hydrogen bromide andheated at reflux under dry nitrogen for 1/2 hour then concentrated. Theresidual oil is crystallized from water to give 5.4 g. of hydrogenbromide salt of the title product with m.p. 268°-272° and [α]_(D) ²⁵ = +41.4°.

Analysis for: C₁₆ H₂₄ NOBr . 1/4 H₂ O Calculated: C, 58.09; H, 7.46; N,4.23 Found: C, 58.20; H, 7.61; N, 4.23.(-)-13β-Amino-5,6,7,8,9,10,11,12-Octahydro-5α-Methyl-5,11-Methanobenzocyclodecen-3-Ol

In the same manner as described for the preparation of the plus rotatingisomer, from the ethereal solution of minus rotating base described inExample LXXX, Part B there is obtained 5.5 g. of hydrogen bromide saltof the title product with m.p. 269°-271° and [α]_(D) ²⁵ = - 41.7°.

Analysis for: C₁₆ H₂₄ NOBr . 1/4 H₂ O Calculated: C, 58.09; H, 7.46; N,4.23 Found: C, 58.47; H, 7.41; N, 4.26.

EXAMPLE LXXXII13β-(Dimethylamino)-5,6,7,8,9,10,11,12-Octahydro-5α-Methyl-5,11-Methanobenzocyclodecen-3-Ol

A solution of 5,6,7,8,9,10,11,12-octahydro-3-methoxy-N,N,5α-trimethyl-5,11-methanobenzocyclodecen-13β-amine, hydrochloride (5.0g.) in 80 ml. of 48% hydrobromic acid is heated at reflux under drynitrogen for 20 minutes then concentrated. The residue is crystallizedfrom ethanol-ether to give 4.4 g. of the hydrobromide salt of the titleproduct m.p. 243°-245°.

Analysis for: C₁₈ H₂₈ NOBr Calculated: C, 61.01; H, 7.96; N, 3.95 Found:C, 61.06; H, 8.10; N, 3.85.

EXAMPLE LXXXIII5,6,7,8,9,10,11,12-Octahydro-3-Methoxy-N,N,5α-Trimethyl-5,11-Methanobenzocyclodecen-13β-AmineN-Oxide

To a cold (0°) solution of5,6,7,8,9,10,11,12-octahydro-3-methoxy-N,N,5α-trimethyl-5,11-methanobenzocyclodecen-13β-amine(1.5 g.) in 20 ml. of dry tetrahydrofuran is added 1.0 g. of metachloroperbenzoic acid in 10 ml. of tetrahydrofuran. The solution isstirred at 0° to 10° for 30 minutes. Two ml. of a saturated solution ofhydrogen chloride in ethanol is added. After crystallization occurs, 30ml. of ether is added and the mixture is filtered to give 1.7 g. of thehydrogen chloride salt of the title product with m.p. 170°-173° dec.

Analysis for: C₁₉ H₃₀ NO₂ Cl Calculated: C, 67.13; H, 8.90; N, 4.13Found: C, 66.61, H, 9.04; N, 3.98.

EXAMPLE LXXXIV6,7,8,9-Tetrahydro-N,5-Dimethyl-5,9-Methano-5H-Benzocyclohepten-10-Amine

In a manner analogous to that described in Example XXXVII for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclononen-12α-aminefrom 1.1 g. of6,7,8,9-tetrahydro-5-methyl-5,9-methano-5H-benzocyclohepten-10-aminethere is obtained 0.90 g. of the hydrogen chloride salt of the titleproduct with m.p. 289°-290 .

Analysis for: C₁₄ H₂₀ NCl Calculated: C, 70.72; H, 8.48; N, 5.89 Found:C, 70.40; H, 8.59; N, 5.93.

EXAMPLE LXXXV 1-(4-Bromobutyl)-1-Ethoxycarbonyl-2-Indanone

In a manner analogous to that described in Example LXXV for thepreparation of 1-(3-bromopropyl)-1-ethoxycarbonyl-2-indanone, from 51 g.of 1-ethoxy-carbonyl-2-indanone there is obtained 41 g. of the titleproduct with b.p. 170 at 0.4 mm.

EXAMPLE LXXXVI 1-Ethoxycarbonyl-1,3-Butano-2-Indanone

In a manner analogous to that described in Example LXXVI for thepreparation of 1-ethoxycarbonyl-1,3-propano-2-indanone, from 45 g. of1-(4-bromo)-1-ethoxycarbonyl-2-indanone there is obtained 14.5 g. of thetitle product with b.p. 140° at 0.4 mm.

EXAMPLE LXXXVII 1-Ethoxycarbonyl-1,3-Butano-2 -Indanone, Oxime

In a manner analogous to that described in Example LXXVII for thepreparation of 1-ethoxycarbonyl-1,3-propano-2-indanone, oxime, from 11g. of 1-ethoxy-carbonyl-1,3-butano-2-indanone there is obtained 5.5 g.of the title product with m.p. 122°-4°.

EXAMPLE LXXXVIII11-Amino-5,6,7,8,9,10-5,10-Methano-Benzocyclooctene-5-Methanol

In a manner analogous to that described in Example LXXXVII for thepreparation of10-amino-6,7,8,9-tetrahydro-5,9-methano-5H-benzocyclopheptene-5-methanol,from 6.6 g. of 1-ethoxycarbonyl-1,3-butano-2-indanone, oxime there isobtained 4.1 g. of the title product as the hydrogen chloride salt withm.p. 197°-200°.

Analysis for: C₁₄ H₂₀ NOCl Calculated: C, 66.26; H, 7.94; N, 5.52 Found:C, 66.40; H, 8.13; N, 5.80.

EXAMPLE LXXXIX5,6,7,8,9,10-Hexahydro-11-Methylamino-5,10-Methanobenzocyclooctene-5-Methanol

In a manner analogous to that described in Example XXXVII for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclononen-12α-amine,from 3.0 g. of 11-amino-5,6,7,8,10,-5,10-methano-benzocyclooctene-5-methanol there is obtained 1.9 g. of thetitle product as the hydrogen chloride salt with m.p. 275°-276°.

Analysis for: C₁ 5H₂₂ NOCl Calculated: C, 67.27; H, 8.28; N, 5.23 Found:C, 67.38; H, 8.46; N, 5.19.

EXAMPLE XC11-Dimethylamino-5,6,7,8,9,10-Hexahydro-5,10-Methanobenzocyclooctene-5-Methanol

In a manner analogous to that described in Example LXIV for thepreparation of5,6,7,8,9,10-hexahydro-3-methoxy-N,5α-dimethyl-5,9-methanobenzocyclooctene-11β-amine,from 1.3 g. of5,6,7,8,9,10-hexahydro-11-methylamino-5,10-methanobenzocyclooctene-5-methanol1.25 g. of the title product as the hydrogen chloride salt, m.p.243°-4°.

Analysis for: C₁₆ H₂₄ NOCl Calculated: C, 68.19; H, 8.58; N, 4.97 Found:C, 67.97; H, 8.67; N, 4.50.

EXAMPLE XCI

To prepare: 1-(5-bromopentyl)-6,7-dimethoxy-1-methyl-2-tetralone react6,7-dimethoxy-1-methyl-2-tetralone with 1,5-dibromopentane as taught inExample I.

To prepare: 1-allyl-1(4-chlorobutyl)- 7-methoxy-2-tetralone react1-allyl-7-methoxy-2-tetralone with 1-bromo-4-chlorobutane as taught inExample I.

To prepare: 7-fluoro-1-(5-bromopentyl)-1-methyl-2-tetralone react7-fluoro-1-methyl-2-tetralone with 1,5-dibromopentane as taught inExample I.

EXAMPLE XCII

To prepare:5,6,7,8,9,10,11,12-octahydro-2,3-dimethoxy-5-methyl-5,11-methanobenzocyclodecen-13-onetreat 1-(5-bromopentyl)-6,7-dimethoxy-1-methyl-2-tetralone with sodiumhydride as taught in Example X.

To prepare:5-allyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-onetreat 1-allyl-1-(4-chlorobutyl)-7-methoxy-2-tetralone with sodiumhydride as taught in Example X.

To prepare:3-fluoro-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methanobenzocyclodecen-13-onetreat 7-fluoro-1-(5-bromopentyl)-1-methyl-2-tetralone with sodiumhydride as taught in Example X.

EXAMPLE XCII

To prepare:5,6,7,8,9,10,11,12-octahydro-2,3-dimethoxy-5-methyl-5,11-methanobenzocyclodecen-13-one,oxime treat5,6,7,8,9,10,11,12-octahydro-2,3-dimethoxy-5-methyl-5,11-methanobenzocyclodecen-13-onewith hydroxyl amine hydrochloride as taught in Example XIX, method C.

To prepare:5-allyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one,oxime treat5-allyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-onewith hydroxyl amine hydrochloride as taught in Example XIX, method C.

To prepare: 3-fluoro-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methanobenzocyclodecen-13-one, oxime treat3-fluoro-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methanobenzocyclodecen-13-one with hydroxyl amine hydrochloride as taught in Example XIX, methodC.

EXAMPLE XCIV5,6,7,8,9,10,11,12-Octahydro-2,3-Dimethoxy-5-Methyl-5,11-Methano-Benzocyclodecen-13-Amine

Using a procedure analogous to that described in Example XXVIIA for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-aminefrom 5.2 g. of5,6,7,8,9,10,11,12-octahydro-2,3-dimethoxy-5-methyl-5,11-methano-benzocyclodecen-13-one,oxime there is obtained 4.17 g. of the title product which is convertedto the hydrogen chloride addition salt m.p. 281°-283°.

Analysis for: C₁₈ H₂₈ O₂ NCl Calculated: C, 66.40; H, 8.67; N, 4.30Found: C, 66.27; H, 8.81; N, 4.23.

EXAMPLE XCV5-Allyl-6,7,8,9,10,11-Hexahydro-3-Methoxy-5,10-Methano-5H-Benzocyclononen-12-Amine

Using a procedure analogous to that described in Example XXVIIA for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine,from 13.3 g. of 5-allyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-one, oxime there is obtained 6.3 g. of the titleproduct which is converted to the fumaric acid addition salt m.p.219°-220°.

Analysis for: C₁₉ H₂₉ NO₅ Calculated: C, 68.19; H, 7.54; N, 3.62 Found:C, 68.42; H, 7.78; N, 3.99.

EXAMPLE XCVI3-Fluoro-5,6,7,8,9,10,11,12-Octahydro-5α-Methyl-5,11-Methanobenzocyclodecen-13β-Amine

Using a procedure analogous to that described in Example XXVIIA for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine,from 14.1 g. of3-fluoro-5,6,7,8,9,10,11,12-octahydro-5-methyl-5,11-methanobenzocyclodecen-13-one,oxime there is obtained 10.5 g. of the title product which is convertedto the fumaric acid addition salt (8 g.) of the title product m.p.218°-220°.

Analysis for: C₂₀ H₂₀ FNO₄ Calculated: C, 66.10; H, 7.21; N, 3.85 Found:C, 65.80; H, 7.26; N, 3.58.

EXAMPLE XCVII3-Methoxy-5α-Methyl-5,6,7,8,9,10,11,12-Octahydro-5,11-Methanobenzocyclodecen-13α-Amine

From the mother liquors remaining after the isolation of the product ofExample XXXV,3-methoxy-5α-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methano-benzocyclodecen-13β-amine,there is obtained by following a procedure analogous to that describedin Example XXXIV part C for the isolation of5,6,7,8,9,10-hexahydro-3-methoxy-5α-methyl-5,9-methano-benzocycloocten-11β-amine,hydrochloride, the title product, m.p. 207°-208°.

EXAMPLE XCVIII3-Methoxy-N,5α-Dimethyl-5,6,7,8,9,10,11,12-Octahydro-5,11-Methanobenzocyclodecen-13α-Amine

In a manner analogous to that described in Example XXXVII for thepreparation of6,7,8,9,10,11-hexahydro-3-methoxy-N,5α-dimethyl-5,10-methano-5H-benzocyclononen-12α-aminethere is obtained from3-methoxy-5α-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzocyclodecen-13α-aminethe title product with an NMR Analysis having an N-CH₃ signal at δ =2,48 ppm. (free base).

EXAMPLE XCIX(-)-13β-Amino-5,6,7,8,9,10,11,12-Octahydro-5α-Methyl-5,11-Methanobenzocyclodecen-3-Ol,Cyclopropanecarboxylate Hydrochloride

A mixture of 5.0 g. of(-)-13β-amino-5,6,7,8,9,10,11,12-octahydro-5α-methyl-5,11-methanobenzocyclodecen-3-ol,hydrobromide, 2.8 g. of carbobenzyloxychloride, 200 ml. of methylenechloride and 200 ml. of a saturated aqueous sodium bicabonate solutionis stirred at room temperature for 2 hours. The methylene chloride layeris separated, dried and concentrated to give an oil which is washed 4times with hexane. The resultant viscous oil is dissolved in 200 ml. ofbenzene and to this stirred solution is added 1.7 g. of trimethylaminefollowed by 1.7 g. of cyclopropane carbonyl chloride in a littlebenzene. After 1/2 hour of stirring the mixture is extracted with water,washed with sodium bicarbonate, dried and concentrated to give a viscousglass. This glassy material is dissolved in 250 ml. of tetrahydrofurancontaining 3.0 g. of dry hydrogen chloride. This solution ishydrogenated over 1.6 g. of 10% palladium on carbon at 45 psi. hydrogenpressure for 3 hours. The catalyst is filtered and the filtrate isconcentrated to give a viscous glass. The glassy material iscrystallized from tetrahydrofuran-ether to give 2.3 g. of white crystalswith m.p. 276°-277° dec. An additional 0.62 g. is obtained from themother liquors on further addition of ether and standing. The analyticalsample had m.p. 278° dec., [α]_(D) ²⁵ = -39.5°.

Analysis for: C₂₀ H₂₈ NO₂ Cl₂ Calculated: C, 68.65; H, 8.07; N, 4.00Found: C, 68.26; H, 7.95; N, 3.95.

The subject matter which the applicants regard as their invention isparticularly pointed out and distinctly claimed as follows:
 1. Acompound of the formula: ##STR15## wherein R is hydrogen, lower alkyl,lower alkyloxy, hydroxy, benzyloxy, halogen, or trifluoromethyl; R¹ islower alkyl, lower alkenyl or phen(lower)alkyl; R² is hydrogen, or loweralkyl; R³ is hydrogen, lower alkyl, alkenyl, or alkynyl; and n is aninteger of from 2 to 6; and the pharmaceutically non-toxic additionsalts thereof.
 2. A compound as defined in claim 1 wherein n =
 3. 3. Acompound as defined in claim 1 wherein n =
 4. 4. A compound as definedin claim 3 which is6,7,8,9,10,11-hexahydro-3-methoxy-5-methyl-5,10-methano-5H-benzocyclononen-12-amine.5. A compound as defined in claim 3 which is12-amino-6,7,8,9,10,11-hexahydro-5-methyl-5,10-methano-5H-benzocyclononen-3-ol.6. A compound as defined in claim 3 which is5-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12-amine.7. A compound as defined in claim 3 which is12-amino-6,7,8,9,10,11-hexahydro-5-ethyl-5,10-methano-5H-benzocyclononen-3-ol.8. A compound as defined in claim 1 wherein n is
 5. 9. A compound asdefined in claim 8 which is3-methoxy-5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzocyclodecen-13-amine.10. A compound as defined in claim 8 which is13-amino-5-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzocyclodecen-3-ol.11. A compound as defined in claim 8 which is(-)-13β-amino-5α-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzocyclodecen-3-ol.12. A compound as defined in claim 8 which is(-)-13β-amino-5α-methyl-5,6,7,8,9,10,11,12-octahydro-5,11-methanobenzocyclodecen-3-ol,hydrobromide.13. A compound as defined in claim 3 which is(-)-5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12β-amine.14. A compound as defined in claim 3 which is(+)-5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12β-amine.15. A compound as defined in claim 3 which is(-)-12β-amino-5α-ethyl-6,7,8,9,10,11-hexahydro-5,10-methano-5H-benzocyclononen-3-ol.16. A compound as defined in claim 3 which is(+)-12β-amino-5α-ethyl-6,7,8,9,10,11-hexahydro-5,10-methano-5H-benzocyclononen-3-ol.17. A compound as defined in claim 3 which is5α-ethyl-6,7,8,9,10,11-hexahydro-3-methoxy-N-methyl-5,10-methano-5H-benzocyclononen-12β-amine.18. A compound as defined in claim 3 which is5α-allyl-6,7,8,9,10,11-hexahydro-3-methoxy-5,10-methano-5H-benzocyclononen-12β-amine.19. A compound as defined in claim 8 which is5,6,7,8,9,10,11,12-octahydro-3-methoxy-N,5α-dimethyl-5,11-methanobenzocyclodecen-13β-amine.20. A compound as defined in claim 8 which is5,6,7,8,9,10,11,12-octahydro-3-methoxy-N,N,5α-trimethyl-5,11-methanobenzocyclodecen-13β-amine.21. A compound as defined in claim 8 which is13β-amino-5,6,7,8,9,10,11,12-octahydro-N,N,5α-trimethyl-5,11-methano-benzocyclodecen-3-ol.22. A compound as defined in claim 8 which is(-)-5,6,7,8,9,10,11,12-octahydro-3-methoxy-5α-methyl-5,11-methanobenzocyclodecen-13β-amine.23. A compound as defined in claim 3 which is12β-amino-6,7,8,9,10,11-hexahydro-5α-methyl-5,10-methano-5H-benzocyclononen-3-ol.24. A compound as defined in claim 3 which is12α-amino-6,7,8,9,10,11-hexahydro-5α-methyl-5,10-methano-5H-benzocyclononen-3-ol.